Immunological Off-Target Effects of Imatinib

REVIEWS
Immunological off-target effects

of imatinib
Laurence Zitvogel1,2, Sylvie Rusakiewicz1,2, Bertrand Routy1,2, Maha Ayyoub1,2
andGuidoKroemer35
Abstract | Around 15years ago, imatinib mesylate (Gleevec or Glivec, Novartis, Switzerland)
became the very first targeted anticancer drug to be clinically approved. This drug constitutes
thequintessential example of a successful precision medicine that has truly changed the fate of
patients with Philadelphia-chromosome-positive chronic myeloid leukaemia (CML) and
gastrointestinal stromal tumours by targeting the oncogenic drivers of these diseases, BCRABL1
and KIT and/or PDGFR, mutations in which lead to gain of function of tyrosine kinase activities.
Nonetheless, the aforementioned paradigm might not fully explain the clinical success of this agent
in these diseases. Growing evidence indicates that the immune system has a major role both in
determining the therapeutic efficacy of imatinib (and other targeted agents) and in restraining the
emergence of escape mutations. In this Review, we reevaluate the therapeutic utility of imatinib in
the context of the anticancer immunosurveillance system, and we discuss how this concept might
inform on novel combination regimens that include imatinib withimmunotherapies.
Gustave Roussy Cancer

Campus (GRCC), INSERM
U1015, 114 rue Edouard
Vaillant, 94805 Villejuif,
France.
2
Center of Clinical
Investigations in Biotherapies
of Cancer, CICBT1428, GRCC,
94805 Villejuif, France.
3
Equipe 11 labelise par la
Ligue Nationale contre le
Cancer, INSERM U1138,
Centre de Recherche des
Cordeliers, University of Paris
Descartes, Sorbonne Paris
Cit, 75006 Paris, France.
4
Ple de Biologie, Hpital
Europen Georges Pompidou,
75015 Paris, France.
5
Metabolomics and Cell
Biology Platforms, GRCC,
94805 Villejuif, France.
1
Correspondence to L.Z.
andG.K.
laurence.zitvogel@
gustaveroussy.fr;
kroemer@orange.fr
doi:10.1038/nrclinonc.2016.41
Published online 31 Mar 2016
Imatinib mesylate (Gleevec or Glivec, Novartis,

Switzerland) exemplifies the successful development of
a therapy that has been rationally designed to target a
single molecular event necessary and sufficient to trig
ger carcinogenesis. Over the past decades, the discovery
of signalling pathways that regulate cell adhesion, cell
growth, the cell cycle and cell death in human malig
nancies identified numerous potential targets, only
a few of which have become clinically relevant across
several neoplasms. Following a better understanding of
chromosomal and genetic changes, transforming retro
viruses, molecular biology techniques and biochemi
cal evaluation of tyrosine kinases, and an increased
understanding of the molecular pathogenesis in can
cer, prompted the birth of precision medicine and a
blockbuster drug for the pharmaceutical industry (FIG.1).
The translocation of the long arms of chromo
somes9 and 22, t(9;22)(q34; q11), creating the socalled
Philadelphia (Ph) chromosome, is found in virtually
all patients with chronic myeloid leukaemias (CML)
and a third of adults with acute lymphoblastic leukae
mia (ALL)1,2. This genetic rearrangement generates the
BCRABL1 fusion gene that encodes an oncogenic, con
stitutively active 210kDa protein tyrosine kinase (PTK),
which underlies the leukaemogenic process3. In the 1990s,
researchers from Ciba Geigy performed high-throughput
screenings of chemical libraries to identify inhibitors of
the ATP-binding pocket, known as tyrphostins. This
effort led to the identification of a lead compound of the
2phenylaminopyrimidine class4, and later on, more-

specific and potent molecules inhibiting PDGFR, ABL1
and KIT PTKs, including imatinib57. AphaseI dose-
escalation study in June 1998 investigated imatinib in
patients with chronic phase, IFNresistant CML8. After
3weeks of daily oral administration of 300mg of imati
nib, no dose-limiting toxicity was observed and 98% of
patients achieved complete haematological responses
with a median duration of 310 days8. Cytogenetic
responses were seen in 53% of patients, including 13%
who had complete remissions, and minimal adverse
effects were noted. The success of this phaseI study in
patients with chronic phase CML, myeloid and lymphoid
blast crisis and patients with refractory or relapsed Ph+
leukaemia prompted phaseII trials accruing thousands
of patients, the results of which served as the basis for
the FDA approval of imatinib on 21May 2001. In 2003,
1,106 previously untreated patients with newly diag
nosed chronic-phase CML were treated in the phaseIII
IRIS trial9. This unprecedented trial confirmed the par
adigm shift in the treatment of CML. Estimated major
cytogenetic response rates at 18months were 87% in the
imatinib arm and 35% in the IFN and low-dose cytara
bine arm (P<0.001); complete cytogenetic response rates
were 76% and 15%, respectively (P<0.001)9. Results from
this pivotal trial were updated at several time points and
at 7years, the event-free survival rate remained above
80% with an estimated overall survival rate of 86%10,11. In
a 10year follow up randomized trial (CML-Study IV),
NATURE REVIEWS | CLINICAL ONCOLOGY
ADVANCE ONLINE PUBLICATION | 1

.
d
e
v
r
e
s
e
r
s
t
h
g
i
r
l
l
A
.
d
e
t
i
m
i
L
s
r
e
h
s
i
l
b
u
P
n
a
l
l
i
m
c
a
M
6
1
0
2
REVIEWS
Key points
Imatinib does not affect Philadelphia-chromosome-positive haematopoietic stem
cells in patients achieving molecular response (MR); however, prolonged relapse-free
survival can be achieved before treatment discontinuation, implying that efficient
immunosurveillance has been established
In addition to targeting tumoural BCRABL1 and KIT oncogene products, imatinib
modulates protein tyrosine kinases involved in key signalling pathways in both
effector and regulatory immune cells implicated in cancer immunosurveillance
Low-dose imatinib has stimulatory effects on haematopoiesis and can contribute to
immune-mediated clearance of pathogens
In patients with chronic myeloid leukaemia, imatinib elicits antigen-specific Tcell
responses that can protect against relapses in patients with cytogenetically
controlled or minimal disease
Imatinib boosts natural killer-cell-induced IFN secretion and decreases regulatory
Tcell numbers in patients with gastrointestinal tumours; NKp30 isoform patterns
dictate the prognosis of the disease
We propose that novel treatment regimens combining imatinib with
immunotherapies will enable long-term relapse-free survival to be achieved in a
larger number of patients and will prevent the emergence of imatinib-resistant clones
the safety and efficacy of imatinib in CML was confirmed

and the authors concluded that imatinib continues to be
an excellent initial therapy for most patients with CML12.
Gastrointestinal stromal tumours (GIST) originate
from interstitial Cajal cells (or their precursors) and
develop as a result of activating KIT mutations (detecta
ble in >75% of patients with GIST), a fact that ignited a
series of trials demonstrating the efficacy of imatinib for
this specific indication. In 2002, imatinib was approved
in the USA and Europe for the treatment of locally
advanced and metastatic GIST1317. The success of imati
nib in patients with CML or GIST18 prompted the era
of molecularly targeted agents and personalized oncol
ogy that led to the development of small-molecule or
antibody inhibitors of the HER2/neu oncogenic kinase
in a subset of patients with breast cancer, EGFR and/or
ALK in patients with non-small-cell lung cancers19, and
the BRAF/MEK pathway in patients with melanoma,
among others. Imatinib-treated cancers developed
escape variants owing to the clonal selection of cells
with secondary mutations or gene amplifications of the
driver oncogene2024, however, and similar observations
were made in breast cancers and melanomas treated with
trastuzumab and vemurafenib,respectively25.
The therapeutic effects of cytotoxic anticancer agents,
as well as those of targeted agents, have been widely
assumed to exert their actions only on malignant cells,
either through their debulking capability (which leads
to partial or complete responses followed by relapse)
or by eradication of all tumour stem cells (which leads
to permanent cure). Imatinib selectively kills Ph +
myeloid-lineage cells in the bone marrow and periphery
because their survival depends on BCRABL1, but does
not affect the survival of Ph+ haematopoietic stem cells
(HSC)26, meaning that the cessation of imatinib treat
ment should lead to relapse. At odds with this specula
tion, findings from the French STIM trial27 showed that
out of 100 patients with CML, 41% could stop imatinib
without relapse after achieving a complete molecular
response lasting 2years. These results were further

corroborated by several independent clinical trials and
updates from the original STIM trial2831. How can this
paradox be explained?
Growing evidence indicates that anticancer agents
can mobilize the immune system against the tumour; for
instance, by inducing immunogenic death of malignant
cells32, by sensitizing such cells to an immune attack33, by
suppressing regulatory immune circuits, or by engaging
activating immune receptors34. By inducing or reinstat
ing immunosurveillance, the activity of conventional and
targeted therapies might be prolonged beyond cessation
of the treatment33. We explore the case of imatinib to
exemplify that targeted anticancer therapies likely oper
ate through off-target or immune, in addition to on
target or cell-autonomous, mechanisms. This concept
has practical implications for defining novel immune-
related biomarkers that predict the response or resistance
to imatinib, as well as for the design of novel combination
treatments of imatinib andimmunotherapies.
Effects of imatinib on haematopoiesis

Elevated white blood cell and platelet counts were
observed during the phaseI trial of imatinib in patients
with Ph+ leukaemias35, and imatinib occasionally causes
a dermal rash associated with local accumulation of
neutrophils (Sweets syndrome) in patients with GIST36.
Imatinib modulates haematopoiesis in a KIT-dependent
manner37, and at different steps in this process in mice,
depending on the dosage used38,39. First, it affects the flux
of HSC and multipotent progenitor (MPP) cell types; sec
ond the maturation of myeloid, but not lymphoid, pro
genitors; and third the migration of mature myeloid cells
to the blood and peripheral organs38,39. Accumulation of
MPP and mature myeloid cells is detected in the bone
marrow at different imatinib doses, although accumu
lation of myeloid cells in the blood occurred only at the
low dose that is associated with upregulation of CXCR2
surface expression on mature neutrophils in the bone
marrow, which facilitates migration of the cells from the
bone marrow to the blood40. The KIT-mediated effects
of imatinib on emergency haematopoiesis are impor
tant as a natural response to infection, whereas inhibition
of ABL1, ABL2 and other imatinib-sensitive receptors
involved in viral and mycobacterial infection4144, as well
as the induction of autophagy45,46, might account for the
clearance of pathogens that has been observed during
imatinib therapy in preclinical models40.
Imatinib-induced immunomodulation
Deleterious myeloid and lymphoid effects
Imatinib can also influence the proliferation, polari
zation and/or function of different subsets of myeloid
and lymphoid cells. By acting on various PTKs (BOX1),
imatinib has a broad-spectrum bioactivity that modu
lates multiple distinct cell types involved in anticancer
immunosurveillance (TABLES1,2). In several invitro
and invivo mouse studies, clinically relevant concen
trations of imatinib (equivalent to 400800mg per
day in humans) have been shown to inhibit the gen
eration of dendritic cells (DCs), which results in less
2 | ADVANCE ONLINE PUBLICATION
www.nature.com/nrclinonc
.
d
e
v
r
e
s
e
r
s
t
h
g
i
r
l
l
A
.
d
e
t
i
m
i
L
s
r
e
h
s
i
l
b
u
P
n
a
l
l
i
m
c
a
M
6
1
0
2
REVIEWS
a The history of the rst TKI in Ph1+ CML
CibaGeigy Lydon
biochemist lead
compound identied
in a screen for PKCi
19901992
First synthesis
of imatinib
First phase I
trials in CML
19961998
In vivo discovery
of tumoricidal
activity in
BCRABL
leukaemia
b The history of the rst TKI in GIST

First patient in
Finland receiving
imatinib for a GIST
19982000
Discovery of
c-Kit mutations
in GIST
First phase I
trials in GIST
May 2001
May 2001: FDA

approval for CML
First demonstration of
an immune o-target
eect of imatinib
June 2000:
phase III trial
20002001
2004
November 2001: approval in

Europe and Japan for CML
Lasker award
presented to Druker,
Lydon and Sawyers
20092011
IFN in combination
with TKI in clinical
trials
Glivec given tradename

Gleevec by Novartis
February 2002: FDA

approval for GIST
Phase IIIII
trials
Discovery
of PDGFR
mutations
in GIST
2002
2004
June 2002: EMEA

approval for GIST
Imatinib
eects on
NK cells
First immune
predictor of response:
NKp30 isoforms
20112014
On-target eect
of imatinib (IDO)
to suppress
TREG cells
Combination of
dasatinib and
ipilimumab in
refractory GIST
Figure 1 |Key time points in the discovery and development of imatinib for the treatment of chronic myeloid
Nature Reviews
Oncology
leukaemia (CML) and gastrointestinal stromal tumour (GIST). a | Development of imatinib
in CML. A| Clinical
new drug
application was submitted 2years and 9months after the first treatment of a patient with CML, triggering the FDA
approval of imatinib within 3months of the initial application. b | Development of imatinib in GIST. Hirota and
co-authors171 first discovered the somatic gain of function mutations of KIT in patients with GIST. A case report18 and the
outstanding results of the phaseI13 and II trials172 of imatinib led to the rapid launch of two phaseIII trials of this agent.
The first off-target effect of imatinib was demonstrated on NK cells in 2004 (REF.69). PKCi, protein kinase C inhibitor;
TKI,tyrosine kinase inhibitor.
efficient in priming of cytotoxic Tcell lymphocytes

(CTLs). These effects were attributed to reduced phos
phorylation of AKT/PKB and nuclear accumulation
of NFB, and were not mediated via inhibition of
PDGFR or KIT4749. In imatinib-treated patients with
CML, incomplete recovery of circulating DC numbers
(despite normalization of VEGF) was observed, suggest
ing that imatinib can inhibit dendritopoiesis invivo50.
CD163+ tumour-associated macrophages (TAM) are
also influenced by targeted agents. Both in primary and
metastatic GIST, analysis of the immune infiltrates by
immunohistochemistry and transcriptional profiling
revealed the presence of TAM51 with an M1like pheno
type that constrains tumour growth52. This favourable
M1like phenotype found in naive tumours shifted
towards an M2 pattern upon treatment with imatinib,
both in human GIST and in relevant mouse models52.
The imatinib-induced M2 reprogramming of TAM
probably results from tumour cell apoptosis (which is
induced by the ontarget activity of imatinib) followed
by the induction of CCAAT/enhancer binding protein
(C/EBP) transcription factors in TAMs interacting with
apoptotic cells52 (FIG.2). In addition, imatinib blunts
Tcell receptor (TCR)-induced Tcell proliferation
and activation invitro, as well as delayed-type hyper

sensitivity invivo53,54 (FIG.2). Furthermore, CD4+, but
not CD8+, Tcells from imatinib-treated patients with
CML produce lower amounts of effector cytokines in
response to TCR-mediated stimulation than those pro
duced by control cells55. The off-target inhibition of the
Brutons tyrosine kinase (BTK) by imatinib might also
explain the clinical observation that imatinib causes a
reduction in the numbers of IgM-producing memory
Bcells, impaired antibody responses to pneumococcal
vaccines56, a general hypogammaglobulinaemia, and
an alteration of the phenotype of bone marrow plasma
cells5760. Several clinical trials have assessed the benefit
of imatinib for the treatment of sclerotic type chronic
GVHD (ScGVHD), which, apriori, argues in favour of
an immunosuppressive activity of the drug (BOX2)61,62.
Based on data from animal models, however, the bene
ficial effects of imatinib in ScGVHD are believed to
depend on its ability to inhibit the TGF- and PDGF
pathways, both of which are involved in the fibrotic
manifestations of the disease62. Together, the findings of
these studies imply that imatinib might, to some degree,
compromise the ability of myeloid and lymphoid cells to
contribute to a protective antitumour immuneresponse.

.
d
e
v
r
e
s
e
r
s
t
h
g
i
r
l
l
A
.
d
e
t
i
m
i
L
s
r
e
h
s
i
l
b
u
P
n
a
l
l
i
m
c
a
M
6
1
0
2
REVIEWS
Box 1 |Imatinib and protein tyrosine kinase signalling in immune cells
The differentiation, proliferation, and effector functions of innate and adaptive immune
cells are orchestrated by intricate signalling pathways involving numerous protein
tyrosine kinases158. The clinical development of imatinib has been guided by its
selectivity for oncogenic variants of ABL1 (BCRABL1) and KIT, although numerous
studies have demonstrated that imatinib can inhibit the unmutated ABL1 protein in
normal immune cells. Indeed, ABL1 and ABL2 are involved in the development of Tcells,
as well as in the function of mature Tcells159. At higher concentrations than those
required for the inhibition of ABL1, imatinib can also inhibit LCK, a kinase that is
essential for signalling via the Tcell receptor160,161, as well as other kinases, including
Bruton tyrosine kinase in Bcells56, macrophage colony-stimulating factor 1 receptor
(CSF1R) in monocytes and macrophages162, and KIT in dendritic cells69. The overall
outcome of imatinib on the antitumour immune response has proved complex, not only
because of the number of potential target signalling pathways in immune cells, but also
owing to their involvement in antagonist populations (effector and regulatory cells),
thedebulking effect causing a reduction in tumour-induced immune tolerance163,
andthe potential immunogenicity of cancer-cell death32
Favourable immune outcomes of imatinib

Despite the aforementioned suppressive effects of imati
nib on defined immune-cell populations, patients with
CML have not been reported to experience recurrent
infections even during long-term therapy with imati
nib8,10. Importantly, several lines of evidence from mouse
and human studies indicate more-complex effects of
imatinib on the overall immune response during ther
apy. For instance, Catellani etal.63 found increased
proportions of bone marrow CD20+CD5+sIgM+ Blym
phocytes and higher plasma levels of IgM targeting
Olinked sugars expressed by leukaemic cells in imatinib
responders compared with nonresponders (FIG.2). Other
investigations have uncovered a role for KIT in DCs that
skews Tcell responses towards a type2Thelper cell
(TH2/TH17) cytokine profile. This immune polariza
tion could be rescued by imatinib, shifting the immune
response to a more-favourable TH1 type profile to enable
tumour eradication64. Imatinib has also been shown to
restore the proportions of TH1/type 1 cytotoxic (TC1)
cells, which is diminished at diagnosis in patients with
CML compared with the populations observed in healthy
individuals, probably as a result of debulking caused by
the drug therapy resulting in reduced tumour-mediated
immunosuppression65. Furthermore, tumour-specific
immune responses dominated by tumour necrosis factor
(TNF)-producing CD4+ Tcells have been detected in
patients with CML who received imatinib66, and effector
memory CD4+ and CD8+ Tcells specific for the BCR
ABL1 antigen were found during long-term imatinib
treatment67, as well as following imatinibwithdrawal68.
Our group has shown that imatinib is a potent trig
ger of natural killer (NK)-cell functions in mice and
humans69. The antineoplastic activity of imatinib against
established primary or metastatic tumours that resisted
the antiproliferative effects of imatinib invitro was mark
edly inhibited by the administration of an antiNK1.1
antibody that depletes NK and Tcells69. Imatinib did
not directly affect mouse NK cells (that did or did not
express KIT) invitro. Instead, this agent stimulated the
capacity of bone-marrow-derived DCs to trigger resting
NK cells, promoting the release of IFN from NKcells
and the activation of splenic NK cells in mice69 (FIG.2).

Moreover, in 49% of 77 patients with GIST, 2months
of imatinib therapy enhanced levels of IFN secretion
by NK cells an immunological predictor of longer
time to disease progression in GIST69,70. Interestingly,
the randomized, open-label, multicentre, phaseIII
ENESTg1 trial in which investigators assessed the
efficacy of nilotinib versus imatinib as first-line ther
apy for GIST showed that imatinib resulted in higher
progression-free survival (PFS) rates71. As these tyrosine
kinase inhibitors (TKIs) have demonstrated unequivo
cal ontarget effects72 and given the importance of the
off-target immune effects of imatinib, particularly on
NK cells, for its clinical efficacy in GIST, the results of
the ENESTg1 trial raised concerns as to whether the
superiority of imatinib is due to drug-related off-target
immune effects. Unfortunately, the ENESTg1 trial was
not designed to assess this end point, which needs to be
investigated in future studies.
Accumulating evidence also suggests that NK cells
might contribute to the cure of CML by sustaining
complete molecular remissions (CMRs), as first indi
cated in preclinical models of the disease73. Binotto and
colleagues74 reported that patients with CML receiving
imatinib showed preferential expression of activating
NK receptors (NKp30, NKp46, NKp80 and NKG2D),
whereas those treated with dasatinib experienced
increased expression of inhibitory receptors in NKcells
(KIR2DL1). These investigators did not observe a cor
relation between the NKreceptor expression profile
and response to therapy; however, they proposed that
these profiles might correlate with or predict disease
control following TKI discontinuation, a postulate that
they are addressing in a large cohort74. In support of this
hypothesis, several clinical trials of imatinib discontinu
ation have demonstrated that higher NKcell numbers
or NKcell function at the time of discontinuation was
associated with prolonged maintenance of the CMR
status7577. Imatinib can also modulate different cell
populations that suppress myeloid and lymphoid cells,
thus contributing to the relief of tumour-associated
immunosuppression. For instance, Balachandran
etal.78 demonstrated in a transgenic mouse model
of GIST that imatinib amplified a pre-existing CTLmediated antitumour response that fully accounted
for its therapeutic activity. Remarkably, these immune
effects resulted from the ontarget inhibition of KIT on
GIST cells, leading to downregulation of indoleamine
2, 3dioxygenase (IDO). IDO generates kynurenine,
which is trophic for regulatory T (TREG) cells. Indeed,
imatinib caused the apoptosis of tumour-infiltrating
TREG cells with the consequent amelioration of the local
CTL:TREG-cell ratio78. In addition, imatinib impaired
expression of the T REG-cells master transcription
factor FoxP3 and immunosuppressive functions of
murine TREG cells invitro and invivo79 (FIG.2). The ele
vated frequency of another suppressive immune cell
population, that of myeloid-derived suppressor cells
(MDSC), found in patients diagnosed with CML can
be explained by the fact that MDSC are derived from
the BCRABL1expressing tumour clones, and are
.
d
e
v
r
e
s
e
r
s
t
h
g
i
r
l
l
A
.
d
e
t
i
m
i
L
s
r
e
h
s
i
l
b
u
P
n
a
l
l
i
m
c
a
M
6
1
0
2
REVIEWS
normalized following imatinib therapy80, probably as a
result of an ontarget effect. Moreover, the Nordic CML
study group81,82 reported that imatinib, as well as dasati
nib, reduced the suppressive functions of MDSC and
restored a TH1like tumour microenvironment.
Collectively, clinical data have shown that long-term
therapy with imatinib can stimulate anticancer responses
mediated by Tcells and NK cells in patients with CML
or GIST, and together with preclinical findings (TABLE1),
outline the likely contribution of innate or adaptive
immune responses to the antitumour effects mediated
by imatinib.
Immune predictors of imatinib response

Tcell and NKcell immune infiltrates
Immunohistochemical and flow cytometric analyses
have revealed that GISTs are infiltrated by CD4+TH1
cells, CD8+TC1 cells and CD56brightCD16dim/NK cells
(FIG.3;TABLE2). Imatinib treatment promotes a loss of
MHC classI molecules from GIST cells (which might

reflect a Tcell-based immunoediting process), a
reduction of intratumoural TREG-cell numbers and the
relocation of NK cells from the stroma to tumour foci,
leading to a marked increase of the NK/TREG cell ratio
insitu83. Importantly, NKcell infiltration into the tumour
and the presence of tumour-infiltrating lymphocytes
(TIL) have both been independently associated with
improved PFS and both ameliorated the prognostic value
of the Miettinen score (which reflects cell-autonomous
GIST characteristics) to predict the clinical outcome in
patients with locally advanced GIST treated with imati
nib83. The imatinib-induced increase of the NK/TREG cell
ratio was more pronounced in the subset of GIST samples
harbouring an exon 11 KIT mutation (S.R., unpublished
data). Further studies are needed to extend these findings
to metastatic GIST and to evaluate the relative contribu
tion of CTL and TREGcells, as well as that of NK cells, for
disease prognosis.
Table 1 | Off-target immunological effects of imatinib in preclinical models

Drug and reference
Model
Tumour subtype
orinfection
Immune bioactivity
Specific comments
Imatinib173
Leukaemia-derived
dendritic cells
CML
After incubation with imatinib,

DC expressed higher levels of
CD1a, CD80, CD83
Enhanced ability for antigen

presentation
Imatinib174
BMderived DCs from

BALB/c mice
A20 lymphoma
Upregulation of antigen
presentation and APCCD4
Tcell response
Overcome tolerance by
potent APC presentation
Imatinib79
BALB/c mice: invitro

analysis of TREG cells and
tumour growth
Leukaemia and
lymphoma 12B1
andA20
TREG cell and FoxP3 expression

were impaired in cells exposed
to imatinib
TREG-cell TCR signalling

downregulated by alteration
of ZAP70 and LAT pathway
Imatinib175
Listeria monocytogenesOVA-based vaccine
Bacterial infection
Loss of OVA-specific TgTCR

memory responses
Loss of IL7R on CD8+ Tcells
Imatinib176
LCMV vaccine with LCMV

gp or VSV infection
Viral infection
Effector antiviral Tcells and

neutralizing antibody titres
not affected
Loss of memory Tcell

responses to viruses
Imatinib versus
nilotinib177
Athymic nu/nu mice
Plexiform neurofibroma
xenograft
Antitumour effects of imatinib

or nilotinib; enhanced splenic
cytotoxicity with imatinib
Off-target effect greater with

imatinib than with nilotinib
ImatinibFlt3L69
C56BL/6 miceantiNK1.1
antibody or W/Wv mice
B16F10, AK7, RMAS
DCNKcell cross talk
Kit signalling in DCs induced

NKcell effector functions
ImatinibIL2
TRAIL proficient versus

deficient tumours
B16F10
IKDC accumulation in tumour

beds
Role of IL15 and NKG2D

inIKDC functions
Mouse GIST
(REF.52)
GIST-bearing mice crossed

to CCR2-, CX3CR1-,
and CSF1Rdeficient or
reporter mice
Imatinib polarized TAMs to

become M2like through the
activation of CCAAT/enhancer
binding protein (C/EBP)
Depletion of TAM is
associated with increased
tumour weight and decreased
TC1cell infiltrates
Imatinib versus CSF1R

inhibitor PLX3397
Wild-type mice and

KitV558/+ mice
Human GIST
xenograft and murine
spontaneous GIST
No effect of the combination

therapy on TAMs
Important tumour fibrosis
Superiority of PLX3397to
inhibit the oncogene
Prophylactic and for

therapy: depletion of CD8+
Tcells
Spontaneous GIST in
KitV558/+ tg mice
Positive role of effector TC1

cells and negative role of
TREGcells
TREG-cell apoptosis in tumour

beds through IDO inhibition
(ontarget effect of imatinib)
(REF.133)
ImatinibantiCSF1R
antibody or CSF1R
inhibitor PLX5622
(REF.178)
ImatinibCTLA4
blockade78
APC, antigen-presenting cell; BM, bone-marrow; CML, chronic myeloid leukaemia; DC, dendritic cell; GIST, gastrointestinal stromal tumours; IDO, indoleamine
2,3dioxygenase; IKDC, interferon-producing killer dendritic cell; LAT, linker for activated T cell; LCMV, lymphocytic choriomeningitis virus; OVA, ovalbumine; TAM,
tumour-associated macrophages; TC1, type 1 cytotoxic T; TCR, T-cell receptor; Tg, transgenic; TRAIL, TNF-related apoptosis-inducing ligand; TREG, regulatory T; VSV,
vesicular stomatitis virus.

.
d
e
v
r
e
s
e
r
s
t
h
g
i
r
l
l
A
.
d
e
t
i
m
i
L
s
r
e
h
s
i
l
b
u
P
n
a
l
l
i
m
c
a
M
6
1
0
2
REVIEWS
Antigen-specific Tcells
Before the TKI era, the main treatment modality for CML
was HSC transplantation (HSCT), and transplantation
remains the main treatment option for patientswho pres
ent with advanced-stage disease and for those whodo not
respond to TKI treatment84. HSCT is considered the only
curative treatment for CML, but is unfortunately associ
ated with greater morbidity and mortality than other
therapies. Remarkably, Tcell depletion before HLAidentical allogeneic bone-marrow transfera proce
dure that is performed to attenuate the graft-versus-host
disease (GVHD) results in an increased rate of relapse
in patients with CML, compared with those who receive
nonT-cell-depleted grafts85. Such relapses could be
avoided by donor lymphocyte infusion (DLI), support
ing the importance of Tcells in the control of CML: the
Table 2 |Off-target immunological effects of imatinib observed in clinical trials

Drug, study and
reference
Tumour type
Immunomonitoring
Remarks
Imatinib70
56
Metastatic GIST
NK cell IFN secretion levels after

2months
DCLPS exvivo stimulation of

circulating NK cells before and after
2months of imatinib
Imatinib versus nilotinib

versus dasatinib
(STIM trial)74
42
CML
NK cell receptor expression
Imatinib associated with expression of

activating NK cell receptors; dasatinib
associated with an inhibitory NK cell
receptor profile
Imatinib discontinuation 105

(EURO-SKI)76
CML
Circulating NK proportions
Increased NKcell counts (n=36

patients) correlated with maintenance
of remission at 6months
Imatinib101
80
Metastatic GIST
Transcriptional profiling in blood
NKp30 isoforms dictate prognosis
Imatinib
36
Primary GIST
Decreased TREG-cell numbers

and expansion of TC1 TILs, better
CTL:TREG-cell ratio
On-target effect by oncogene

deaddiction leading to decreased
IDOexpression
Imatinib83
67 localized
24 metastatic
Locally advanced Intratumour location of TH1, TREG and

and metastatic
NK cells (IHC) and flow cytometry of
GIST
TIL in fresh tumours
Imatinib induced relocation of NK cells

into tumour nests; MHC classI loss and
TREG depletion
Imatinib179
6 at diagnosis
9 after imatinib
Chronic-phase
CML
Restoration of plasmacytoid DC
differentiation
Production of typeI IFN by

plasmacytoid DC
Imatinib63
32 responders and
8nonresponders
CML
CD5+CD20+sIgM+Bcells, and BAFF,

SDF1, and BMP7 in BM
Natural IgM titres killing leukaemic cells

and associated with clinical benefit
Imatinib long- term

therapy67
10
Ph+ ALL
Emergence of BCRABL1specific
CTLs in BM
Only in molecular remission
Imatinib versus nilotinib

versus dasatinib180
28
CML
Increase GrzB+ TH1 TEM in blood

with dasatinib
No effects of imatinib nor nilotinib on

TEM
Imatinib versus
dasatinib153
54
CML
Normalization of Bcell, DC and NK

cell counts in blood post TKIs
Subset of dasatinib-treated patients

exhibiting activated CD8+Tcells, CNK
and NK cells
Imatinib versus
dasatinib81
(Nordic clinical trial)
Imatinib: n=18
Dasatinib: n=14
CML
Decrease in CD11b+CD14CD33+
MDSCs numbers and inhibitory
molecules, with increased CD40
expression
Increased levels of CD40, IL12, NK cells,

and experienced Tcells comparable
between imatinib and dasatinib
Imatinib
discontinuation75
Imatinib discontinuation
for >6months: n=16; or,
CMR while on treatment
for >2years: n=14
CML
Increased circulating NKcell and

decreased CD8+CD62L+ Tcells
numbers
Mainly in molecular remission
Imatinib
discontinuation181
9 (discontinued imatinib
after an MMR >2years)
CML
Persistence of CD8+TEM in blood
4 patients relapsed and the remaining

5 patients remained in MMR without
imatinib
Imatinib+rIL2 (REF.141)
n=17 (phaseI trial)
Advanced solid
malignancies
Increased CD4+:CD8+ ratio and

circulating HLADR+TRAIL+ NK cells
associated with prolonged TTP
Cyclophosphamide added at the first

cycle
Imatinib+rIFN-2b132
n=8 (pilot study)
Imatinib
refractory GIST
TH1 and TC1 TILs

IFN+ NK cells
High partial and complete response

rates in interim analysis
Imatinib versus IFN119
10 and 16 (+p210/QS21/
GMCSF vaccine)
CML
DTH responses and recall CD4+

Tcell responses to p210
Maintenance of Tcell responses to CML

antigens
78
ALL, acute lymphocytic leukaemia; BM, bone marrow; CML, chronic myeloid leukaemia; CMR, complete molecular remission; CNK, conventional natural killer;
DC,dendritic cell; DTH, delayed type hypersensitivity; GIST, gastrointestinal stromal tumours; IHC, immunohistochemistry; LPS, lipopolysaccharide; MDSC,
myeloid-derived suppressor cells; MHC, major histocompatibility complex; MMR, major molecular response; NK, natural killer; TC1, type 1 cytotoxic T; TEM, effector
memory Tcells; TH1, type 1 helper T; TIL,tumour-infiltrating lymphocyte; TKI, tyrosine kinase inhibitor; TREG, regulatory T; TTP, time to treatment progression.
.
d
e
v
r
e
s
e
r
s
t
h
g
i
r
l
l
A
.
d
e
t
i
m
i
L
s
r
e
h
s
i
l
b
u
P
n
a
l
l
i
m
c
a
M
6
1
0
2
REVIEWS
CTL tness: killing
TH1 cytokine release
Imatinib
CD28
TREG apoptosis Imatinib
CSF1R
TCR
IDO,
arginase,
CCL2
Mutated
c-Kit or
PDGFR
IDO
NKG2D
ligands
Pro-angiogenic
Pro-broblastic
NKp30
sB7-H6
KIR
B7-H6
Tumour
cell
M2 macrophage
MHC
class I
NK cell anergy
VEGF
Blockade of
T-cell priming
MDSC
Imatinib
TCR signalling
and TEM
responses
Memory B cells
BM CD20+CD5+
sIgM+ B cells
Imatinib
c-Kit
DC dierentiation
DC and NK cell
crosstalk
c-Abl1
and Abl2
LCK
BTK
B cell
Nature Reviews | Clinical Oncology
Figure 2 | Effects of imatinib on components of the anticancer immunosurveillance system. The ontarget effect
of imatinib on oncogenic protein tyrosine kinases (PTKs) is accompanied by decreased expression of indoleamine
2,3dioxygenase (IDO), reduced kynurenin secretion, and the subsequent apoptosis of regulatory T (TREG) cells and relative
expansion of cytotoxic Tcell lymphocytes (CTL), as well as by reduced secretion of VEGF and subsequent antiangiogenic
effects. This direct effect of imatinib also reduces NKG2D ligand expression on neoplastic cells, thereby compromising
their recognition by NKG2Dexpressing natural killer (NK) cells (upper left panel). Myeloid-derived suppressor cell (MDSC)
populations in patients with chronic myeloid leukaemia (CML) at diagnosis, which can be derived from the tumour clone
bearing the BCRABL1 fusion gene, are normalized following imatinib therapy or as a result of reduced VEGF serum
concentrations (upper panels). The imatinib-induced reprogramming of tumour-associated macrophages (TAMs) to an M2
phenotype is an on target process, which involves TAM interaction with apoptotic tumour cells (right upper panel). By
targeting KIT on dendritic cells (DCs), imatinib reduces spontaneous and FLT3Linduced DC differentiation, but permits
DCNK cell crosstalk in lymph nodes and the spleen (lower left panel). Imatinib targets ABL1 and ABL2, as well as LCK,
which are involved in Tcell development and the function of mature Tcells, contributing to decreased Tcell receptor
(TCR)-mediated Tcell proliferation and activation invitro and blunted delayed-type hypersensitivity invivo (lower right
panel). The off-target inhibition of Bruton tyrosine kinase (BTK) by imatinib induces reductions in IgM-expressing
memory-Bcell frequency, hypogammaglobulinaemia, and impaired humoural responses to vaccines. Imatinib can,
however, also promote expansion of a specific bone marrow subset of CD20+CD5+sIgM+ B lymphocytes, inducing higher
plasma levels of IgM specific for Olinked sugars expressed by leukaemic cells (lower right panel).
graft-versus-leukaemia (GVL) effect. Intense research has

been conducted in the HSCT field to identify immunecell populations, immune signalling pathways, and anti
gens to uncouple GVHD from GVL responses. Among
the Tcell targets underlying both GVHD and GVL
responses in HLA-identical transplantation are minor
histocompatibility antigens (mHAgs) that correspond to
polymorphic peptides resulting from single-nucleotide
polymorphisms, base-pair insertions and/or deletions
or copy-number variations, that are presented by HLA
molecules and recognized by the donor Tcells. On

the basis of their expression profile, mHAgs have been
divided into two major categories: broadly expressed
versus haematopoietic-restricted mHAgs, with the
latter considered to have higher therapeutic potential
because they are expected to induce a more-vigorous
antitumour immune response86. Multicentre analyses
of data from more than 800 HLA-identical and HLAmatched unrelated-donor HSCT recipients have shown
that mismatching for haematopoietic-restricted mHAgs

.
d
e
v
r
e
s
e
r
s
t
h
g
i
r
l
l
A
.
d
e
t
i
m
i
L
s
r
e
h
s
i
l
b
u
P
n
a
l
l
i
m
c
a
M
6
1
0
2
REVIEWS
Box 2 | Characteristics of imatinib-induced tumour-cell demise
Some conventional anticancer agents can induce tumour-cell stress and death, causing
cells to present or secrete danger-associated molecular patterns (DAMPs) that alert the
innate-immune system, thereby stimulating an anticancer immune response. This
applies to chemotherapeutic agents, such as anthracyclines and oxaliplatin164,
as well as to photodynamic stress165. The underlying mechanisms leading to such an
immunogenic cell death are heterogeneous, but the DAMPs linking immunogenic cell
death to the activation of dendritic cell precursors seem to be mostly chaperones (such
as calreticulin and heat-shock proteins), chemotactic factors (such as ATP), alarmins (for
example, HMGB1), and typeI interferons. Imatinib induces an autophagic response in
tumour cells expressing BCRABL1 or activated KIT45,46,166, and autophagy is a
prominent feature of immunogenic cell death because it facilitates the release of ATP
from dying tumour cells167,168. Imatinib can also induce caspase-independent cell death
with necrosis-like features in BCRABL1positive human leukaemic cells169; necrotic cell
death has prominent pro-inflammatory and perhaps immunogenic properties170,
although this has not been investigated in depth for imatinib-induced cell death.
is correlated with higher relapse-free and overall sur

vival87. Interestingly, this correlation held true only in
patients experiencing GVHD87. Thus, although these
results demonstrate the difficulty in dissociating GVL
from GVHD, they support the development of immuno
therapy approaches aimed at enhancing Tcell responses
to mHAgs to tip the balance towards GVL. Our under
standing of mHAgs is growing rapidly thanks to the avail
ability of data from genome-wide association studies that
enable the assessment of the full spectrum of potential
mHAgs88. Nonetheless, while mHAgs represent highly
pertinent targets for GVL enhancement, their relevance
is limited to the HSCT setting and no data are avail
able regarding the influence of treatment with imatinib
following HSCT on Tcell responses tomHAgs.
The second category of antigens of interest for CML
relates to those specifically or preferentially expressed
in tumour cellsthat is, tumour-associated antigens.
Several antigens specifically expressed by CML cells can
elicit Tcell responses, and include BCRABL1 (REF.89);
Wilms tumour protein (WT1)90; proteinase 3 (REF.91);
members of the cancer testis antigen (CTA) group, such
as PRAME9294 and HAGE95,96; as well as antigens iden
tified as the targets of high-titre plasma antibody97,98 or
CTL99 responses observed in patients with CML fol
lowing DLI. Interestingly, plasma from DLI responders
also contains a factor that can prime CML-specific CTL
through Toll-like receptor 8 (TLR8)/TLR9dependent
activation of innate immune cells. This immunostimu
latory factor was purified and found to comprise a com
plex that contains antibodies, CML antigens and nucleic
acids100, emphasizing the probable importance of inte
grated innate and adaptive Bcell and Tcell responses
for the clinical efficacy of DLI. However, robust studies
assessing the role of Tcell responses to CML anti
gens in patients with clinical responses to imatinib are
stillawaited.
NKp30 isoforms
Comprehensive phenotyping of peripheral-blood and
GIST-infiltrating NK cells revealed the selective reduc
tion of the expression of one particular NKcell cytotoxic
receptor: NKp30 (REFS70,101). Our group showed that
the alternative splicing of exon4 of the gene encoding

NKp30, which affects the signalling and function of this
receptor, determines the prognosis of patients with meta
static GIST treated with imatinib83. Three major NKp30
isoforms exist, each exhibiting a specific intracytoplas
mic domain: NKp30A, NKp30B, and NKp30C. NKp30A
and NKp30B signalling mediates cytotoxicity and
IFN/TNF production, respectively, whereas signal
ling via the NKp30C isoform induces the productionof
the immunosuppressive cytokine IL10. An imbalance
of the relative transcription of the NKp30 isoforms B and
C (decreased B or increased C, leading to a low B:C iso
form ratio) negatively affects the prognosis of patients
with metastatic GIST treated with imatinib101. The B:C
isoform ratio constitutes an independent predictive fac
tor of response to therapy. Future studies must validate
the prognostic significance of the transcription levels
of NKp30 isoforms in NKp30dependent malignancies
that are amenable to NKstimulatory measures, including
TKI therapy.
sBAG6 and sB7H6 serum markers

Given the prognostic value of NKp30 isoforms in locally
advanced and metastatic GIST101, the prognostic signifi
cance of NKp30 ligands on tumour cells, and the shedding
of these ligands into serum/plasma have been studied.
Several ligands have been proposed to bind to NKp30,
including the intracellular proteins BCL2associated
anthanogene 6 (BAG6)102. BAG6 protein has been identi
fied on the plasma membrane of DCs and transformed
cells, where it can interact with activating NKp30 recep
tors presented on NK cells. Tumours can secrete soluble
variants of BAG6 (sBAG6) endowed with immunosup
pressive function, as well as exosomes containing BAG6
on their surface, which activate NKcell cytotoxicity.
BAG6 has been viewed as an important therapeutic tar
get capable of shaping immune responses or that could
overcome immune-escape strategies in cancer103105.
In patients with CLL, sBAG6 plasma levels increase at
advanced stages of the disease105. Further s tudies are
needed to assess whether imatinib treatment influences
sBAG6 plasma levels and if levels of this protein can be
predictive of response to therapy.
Another NKp30 ligand present on the surface of a
variety of tumour cells (lymphoma, myeloid and Tcell
leukaemias), but not in healthy tissues, has been identi
fied as natural cytotoxicity triggering receptor 3 ligand 1,
NCR3LG1 (best known as B7H6), a B7 family member.
The interaction of NKp30 on NK cells with B7H6 on
target cells stimulates IFN production by NK cells and
favours target-cell killing106. In patients with metastatic
GIST harbouring high serum concentrations of sB7H6
at diagnosis, therapy with imatinib markedly decreased
levels of this protein by 4months (S.R., unpublished
data). Sera from patients with GIST containing sB7H6
dampened the NKp30dependent effector functions of
NK cells from healthy volunteers107, underscoring the
potential relevance of NKp30 ligands in this malignancy.
Multivariate analyses addressing the predictive value of
sNKp30L, NKp30 isoforms, and the mutational status
ofPTKs for the clinical outcome areunderway.
.
d
e
v
r
e
s
e
r
s
t
h
g
i
r
l
l
A
.
d
e
t
i
m
i
L
s
r
e
h
s
i
l
b
u
P
n
a
l
l
i
m
c
a
M
6
1
0
2
REVIEWS
a
c-KIT
HLA-I
CD69+
TNF,
IFN
IDO
FOXP3+
IL-10 and
TGF
TReg cell
CD4+ T cell
TNF,
IL-6 and
IL-1
GIST
TNF,
IFN
CSF1R
CD69+
CD8+ T cell
M1 macrophage
Fibrous trabeulae
TNF,
IFN
CD56hi
NKp80hi
CD69+
NK bright
Imatinib
IDO
CD69+
FOXP3+
IL-10 and
TGF
TNF,
IFN
TNF,
IFN
TNF, IL-6
M2 macrophage
TNF,
IFN
and IL-1
Imatinib
CD56hi
NKp80hi
CD69+
TNF,
IFN
NK bright
Figure 3 | Natural and imatinib-induced immunosurveillance in gastrointestinal tumours (GISTs). a | Natural

immunosurveillance in GIST. GIST contain regulatory T (TREG) cells, as well as CD4+ type1 helper Tcells (TH1), CD8+ type1
cytotoxic Tcells (TC1 cells) located in the tumour nests surrounded by CD56bright CD16dim/ natural killer (NK) cells. b | Effects
of imatinib on the tumour microenvironment. Imatinib promotes a loss of MHC classI molecules, which might reflect the
T-cell-mediated elimination of MHCIpositive tumour cells and hence an example of immunoediting. Imatinib can
reduce intratumoural TREG-cell numbers and cause a relocation of NK cells from the stroma to tumour foci, leading to a
marked increase of the NK:TREG cell ratio insitu. The imatinib-induced increase of the NK:TREG-cell ratio is more pronounced
in the subset of GIST harbouring an exon 11 KIT mutation83.

.
d
e
v
r
e
s
e
r
s
t
h
g
i
r
l
l
A
.
d
e
t
i
m
i
L
s
r
e
h
s
i
l
b
u
P
n
a
l
l
i
m
c
a
M
6
1
0
2
REVIEWS
Immunosuppression and VEGF
VEGF is not only an angiogenic factor and a growth
and survival factor for leukaemic blasts, but also medi
ates broad immunosuppressive activities108110. Imatinib
inhibits VEGF transcription by targeting the Sp1 and
Sp3 transcription factors111. Indeed, the amplification of
BCRABL1 in imatinib-resistant cells is associated with
elevated VEGF expression, which can be suppressed by
escalating the dose of imatinib. The potential prognos
tic value of plasma VEGF concentrations in patients
with CML treated with imatinib has been analysed in
a prospective clinical trial. In the SPIRIT study112, the
French CML group compared the antileukaemic effects
of several imatinib-based combinatorial regimens
in 403 patients with CML, and reported that plasma
VEGF level at diagnosis was an independent predictor
of BCRABL1 burden, with low levels associated with
longer PFS. Of note, the most pronounced drop in cir
culating VEGF concentrations was achieved in the arm
combining imatinib and recombinant IFN-112, which
is the only interferon that is approved for clinical use.
Future prospects
Considering the molecular basis of tumour resistance to
TKIs, various strategies targeting malignant cells have
been attempted to overcome drug resistance113,114. Despite
the putatively deleterious off-target effects ofimatinib on
different immune subsets, the absenceof opportunistic
infections in patients following long-term imatinib treat
ment and their ability to respond to immunotherapies
(such as IFN and DLI) suggest that such patients pos
sess an intact immune system that could be harnessed
to consolidate innate and adaptive immune responses
against the tumour, hence enabling long-term remis
sions or cures after TKI discontinuation. Nonetheless, to
date, immunotherapy with vaccines, NKcell-stimulatory
cytokines, immune-checkpoint blockade or NKp30
targets (FIG.4) have not been implemented in routine
clinical practice.
Vaccination strategies and imatinib
Despite the inability of imatinib to eliminate Ph+ HSC,
therapy discontinuation does not lead to relapse in
40% of patients, suggesting the establishment of adap
tive immune responses with long-term memory2731,115.
Furthermore, results of trials indicate that the deep
molecular response rates achieved in patients with CML
treated with imatinib could warrant therapy discontin
uation in most cases12. The assessment of CML-specific
Tcell responses directed at known or currently unidenti
fied CML antigens in these patients will help define the
role of imatinib-induced Tcells in the definitive cure of
CML. Implementation of immunotherapy approaches
aimed at the enhancement of Tcell responses to the
most-meaningful antigens could increase the proportion
of patients experiencing relapse-free survival following
imatinib discontinuation.
The identification of CML-specific tumour antigens
has provided the opportunity to perform vaccine trials,
most of which dealt with vaccines comprising peptide
epitopes spanning the BCRABL1 fusion region116,117.
In several phaseI and phaseII trials, cellular immunity

against BCRABL1 epitopes resulted in clinical responses
in patients who were treated concomitantly with vaccines
and imatinib118,119; however, larger randomized clinical
trials are necessary to assess the immunological and clini
cal efficacy of these combination therapies. The develop
ment of particularly potent immunological adjuvants120,
together with that of whole-antigen vaccines121,122, offers
promising opportunities for vaccine trials that include
all patients with CML, regardless of their HLA g enotype
in contrast to the situation for the BCRABL1 pep
tides, which are presented by a limited number of HLA
molecules. One particularly promising candidate for
therapeutic vaccination is the CTA PRAME, which is
expressed in about half of patients with CML92, under
the control of BCRABL1, and is associated with a dis
mal prognosis92,123. Other members of the CTA group are
also frequently expressed in patients with GIST, and are
associated with early recurrence or resistance to imati
nib124,125, offering opportunities to investigate vaccines
that could be administered at early stages of the disease,
before the end of the first year of imatinib therapy.
Immunostimulatory cytokines and imatinib

Before the TKI era, IFN was the standard frontline
therapy for patients with CML. IFN as a single agent
is not curative; however, long-term cytogenetic remis
sions have been documented occasionally in patients126.
Several studies have attempted to revive IFN therapy,
which targets leukaemic stem cells, in combination with
imatinib, which affects Ph+ cells of the myeloid lineage.
This combination was assessed using pegylated IFN-2a
in the French SPIRIT study127 and using IFN in the
German CML-study IV128. The results of the SPIRIT
study demonstrated a higher molecular response rate
to the combination therapy in comparison with imati
nib monotherapy; however, no increase in the overall
survival of patients was observed129. By contrast, the
CML-study IV did not reveal an advantage for the com
bination therapy in terms of molecular responses128. The
differences between the two studies might be attributable
to the different forms of IFN used as well as to differ
ences in imatinib dosing. Several subsequent smaller
trials have also yielded contrasting data126. Ofnote, in
all trials, dose adjustments and high discontinuation
rates (>20%) have been reported and attributed to
IFNrelated adverse events126,130. Ongoing trials are in
progress to assess whether low-dose weekly pegylated
IFN-2b in combination with a second-generation TKI
is associated with less toxicity than the combination regi
mens tested in previous trials. Interestingly, Burchert
and colleagues131 have observed an association between
IFN therapy and the induction of proteinase3specific
CTL responses in a cohort of patients whose responses
were maintained under IFN therapy following initial
imatinibIFN combination therapy.
The combination of imatinib and pegylated IFN-2b
has also been assessed in patients with advancedstage GIST. Interim analysis of samples from eight
patients demonstrated significant induction of TH1and
NK cells in the blood and tumour beds132. After a
.
d
e
v
r
e
s
e
r
s
t
h
g
i
r
l
l
A
.
d
e
t
i
m
i
L
s
r
e
h
s
i
l
b
u
P
n
a
l
l
i
m
c
a
M
6
1
0
2
REVIEWS
a
ICB antagonistic antibodies
Co-stimulatory agonistic antibodies

and bi-specic antibodies
CD40
APC
CTLA4
TCR
CTLA4
TCR
PD-L1
or PD-L2
APC
PD-1
PD-1
LAG3
KIR
CD28
TIM3
CD28
PD-L1
or PD-L2
TIM3
Bispecic antibodies
B7-H6 or KIT
CD3
LAG3
KIR
CD28
NKp30 or anti-B7-H6 CAR T cells
Vaccines (BCR-ABL, PRAME, neo-antigens)
CD40
MHCpeptide
TCR
APC
APC
T cell
B7
NK-cell-stimulatory
cytokines (IFN type I, IL-15)
e Re-establishing immuno-
genecity and adjuvanticity
APC
Re-establishing
MHC class I
IDOi
KIT
IDO
Flt3L
Anti-CSF1R KIT
Restoring DC
Blocking M2
IFN/
IFN
Chloroquine
B7-H3 PD-L1?
Autophagy
inhibition
CD28
Adjuvant (TLR agonists,

CTLA-4 blockade)
f
TKI
NK-cell
stimulation
Blocking TREG
Reversing
NKp30
phenotype
Novel ICB
Bispecic ICB
Reprogramming
the inltrate
anti-CSFR1, CSF1,
anti-IL-10, anti-FAP etc.
Antagonistic
antibodies
Figure 4 | Combination immunotherapeutic approaches with imatinib. Several complementary treatment approaches
could be envisioned in combination with first-generation or second-generation tyrosine kinase inhibitors (TKIs). The Tcell
arm of immune responses could be ameliorated with peptidebased or protein-based vaccines, with immune-checkpoint
inhibitors (such as the anti-cytotoxic-Tlymphocyte-associated-antigen4 antibody ipilimumab, which depletes TREG cells
in the tumour), with dendritic cell (DC) growth factors (such as FLT3L) and DC adjuvants (such as Toll-like receptor (TLR)
agonists, antiCD40 agonistic antibodies, or others). The natural killer (NK)-cell arm of immunity could be boosted with
NKcell-stimulatory cytokines (such as IL15 or typeI interferon), with anti-KIR antibody or antiIL10 antibody, mostly in
patients with an unfavourable NKp30 isoform profile. Chimeric antigen receptor (CAR) Tcells can be engineered to
express the extracellular domain of NKp30 or antibodies recognizing B7H6 to promote killing of cells expressing NKp30
ligands and B7H6, respectively. Blocking indoleamine 2,3dioxygenase (IDO) enzymatic activity or reprogramming
M2type tumour-associated macrophages (TAM) using antiCSF1R (macrophage colony-stimulating factor 1 receptor)
orsmall-molecule inhibitors of CSF1R signalling could be instrumental in preventing the proangiogenic and/or
profibroblastic effects of TAM after TKI therapy. ICB, immune checkpoint blockade; KIR, killer IgG-like receptor.

.
d
e
v
r
e
s
e
r
s
t
h
g
i
r
l
l
A
.
d
e
t
i
m
i
L
s
r
e
h
s
i
l
b
u
P
n
a
l
l
i
m
c
a
M
6
1
0
2
REVIEWS
median followup of 3.6years, one patient died of an
unrelated illness while in remission, and six of seven
evaluable patients had ongoing partial or complete
responses (five patients), or had a PFS duration (one
patient) exceeding the expected genotype-specific-PFS,
based on the phaseIII imatinib monotherapy trial data
(CALGB150105/SWOGS0033)132. This highly promising
pilot study underscores that the combination of imati
nib and IFN warrants further development in patients
withGIST132.
Given the capacity of imatinib to boost NKcell func
tions, our group analysed the combination of imatinib
with IL2, an NKcell-stimulatory cytokine. When com
bined with IL2, imatinib induced the intratumoural
accumulation of a subset of premature NK cells, a CD3
CD19B220+CD49b+CD11cdimMHC classII+ subpopula
tion, which is endowed with antigen presenting as well as
TRAIL-dependent lytic functions133136the latter upon
trans-presentation of IL15 by IL15R137,138. On the basis
of synergistic anticancer activity of the combination of
imatinib with IL2 in metastatic tumour models139, we
launched a phaseI clinical trial in 17 patients with refrac
tory solid malignancies to determine the maximum toler
ated dose (MTD) of recombinant IL2 (rIL2) combined
with metronomic cyclophosphamide and imatinib140,141.
rIL2 markedly changed the pharmacokinetics of imati
nib, increasing the blood concentrations of its main
metabolite. Conversely, when combined with imatinib,
the MTD of rIL2 was reduced to 6 MIU daily for 5 con
secutive days. The combination therapy markedly dimin
ished the absolute counts of circulating Bcells, CD4+
Tcells and CD8+ Tcells in a dose-dependent manner;
NK cells upregulated HLADR, TRAIL, and CD56 sur
face expression. Importantly, the abundance of HLADR+
NK cells after one course of combination therapy was
positively correlated with the PFS and overall survival of
patients141. This combinatorial regimen warrants further
investigation in phaseII clinical trials, possibly in patients
with GIST, a setting in which Tcells and NK cells seem
to have an important therapeutic role.
Immune-checkpoint blockade and imatinib

Inhibitory receptors expressed by immune cells con
tribute to the physiological containment of immune
responses142. These receptors are often overexpressed
in Tcells of patients bearing tumours of different his
tological types, and their ligands can be expressed in
tumour cells or other tumour-infiltrating cell types to
limit the efficacy of antitumour immune responses. The
success of clinical trials assessing monoclonal antibodies
that inhibit signalling through two of these receptors,
cytotoxic Tlymphocyte-associated antigen 4 (CTLA4)
and programmed cell-death protein 1 (PD1), led to
the approval of several of these agents for the treatment
ofmetastatic melanoma and lung cancer143. The field of
immune-checkpoint immunotherapy is evolving rapidly,
with clinical trials assessing the usefulness of approved
agents in other clinical settings and with new antibodies
that target numerous other immune checkpoints under
development144. Preclinical studies suggest that these
immune-escape mechanisms could be relevant in CML.
For example, preclinical data demonstrated that PD1

is expressed at significantly higher levels on circulat
ing CD8+ Tcells in patients with CML compared with
healthy volunteers145. A phaseIb clinical trial is currently
enrolling patients to determine the safety and efficacy
of dasatinib plus the antiPD1 antibody nivolumab in
patients with CML (NCT02011945)146. In light of pre
clinical findings showing a role for IDO inhibition in
augmenting the CTL:TREG-cell ratio post-imatinib ther
apy, Balachandran etal.78 combined imatinib with the
firstinclass immune-checkpoint inhibitor, the antiCTLA4 monoclonal antibody ipilimumab, in KitV558/+
transgenic GIST mice, and showed synergistic anticancer
effects (TABLE1) in accordance with other reports147. No
data describing the expression levels of PD1 on TILs
and PD1 ligand 1 (PDL1) or PD1 ligand2 (PDL2)
in GIST are available. Hence, combining a TKI with
CTLA4 blockade might represent a strategy to pri
oritize in patients with advanced-stage GIST, and is
being assessed in two clinical trials (NCT01643278,
NCT01738139)148,149.
Exploiting the B7H6NKp30 axis

B7H6 is expressed on various primary human tumours,
including leukaemias, lymphomas, neuroblastomas and
GISTs, but is not constitutively expressed on normal tis
sues107. Sentmans group pioneered the exploitation of this
axis in preclinical models using chimeric antigen receptor
(CAR) Tcells and the bispecific Tcell engager (BiTE)
approaches. In the CARTcell approach, Tcells are trans
duced with an artificial receptor construct that interacts
with a tumour-antigen expressed on target cells, promot
ing activation of the Tcell that ultimately triggers lysis
of the target cell. In the BiTE approach, a bispecific anti
body bridges a tumour-cell-surface antigen to the TCR
of a Tcell, triggering the lytic process150. NKp30CD8
(or CD28)-CD3 receptors were constructed by joining
the extracellular domain of NKp30 to the transmem
brane domain of human CD8 (amino acids 183203)
or CD28 (amino acids 153220), together with the sig
nalling domain of the TCR CD3chain. All constructs
resulted in NKp30 surface expression and IFN pro
duction following engagement of chimeric NKp30 with
B7H6 positive targets151. Intwo pioneering studies, treat
ment with a B7H6specificBiTE or with B7H6 targeted
CAR Tcells greatly enhanced the survival of mice bearing
B7H6expressing lymphoma, melanoma and ovarian
cancers throughperforin-dependent and IFNdependent
effector mechanisms. These mice mounted memory Tcell
responses against tumour antigens and did not develop
cancers upon subsequent injection of B7H6negative
syngeneic tumours152,150. Moreover, these approaches did
not result in pro-inflammatory DCs and monocytes (that
may express B7H6) being eradicated152,150.
Conclusions
A number of arguments support the notion that imatinib,
the first compound used in precision medicine, exerts
beneficial off-target effects on the immune system that
have contributed to its therapeutic success. First, ample
evidence from mouse models indicates that imatinib and
.
d
e
v
r
e
s
e
r
s
t
h
g
i
r
l
l
A
.
d
e
t
i
m
i
L
s
r
e
h
s
i
l
b
u
P
n
a
l
l
i
m
c
a
M
6
1
0
2
REVIEWS
other TKIs only mediate long-term anticancer effects in
a context in which NK cells and T lymphocytes are fully
functional. Second, in patients with GIST, the compo
sition and function of the NKcell and Tcell infiltrates
of the tumour predicts clinical outcome after imatinib
treatment83,101. Third, the functional competence of NK
cells (and relative expression of NKp30 isoforms) dic
tates the long-term fate of patients with GIST treated with
imatinib. Fourth, imatinib affects the composition of the
immune infiltrate of GISTs, and this dynamic parameter
affects clinical outcome83. Fifth, imatinib can cause atypi
cal stress and death of CML orGIST cells, and this might
contribute to priming and/or recruitment of innate-im
mune effectors. Sixth, imatinib directly and indirectly
inhibits TREG cells and MDSCs, hence removing a major
break on anticancer immunity. Some evidence exists
that TKIs targeting the same receptor kinases as imati
nib can stimulate tumour-specific NKcell and Tcell
responses81,153 (TABLE2); however, it remains to be seen
whether other TKIs can stimulate anticancer immune
responses. BRAF inhibitors might stimulate anti-
melanoma immune responses, which might prolong the
clinical efficacy of these agents154.
Imatinib and next-generation agents have mediated
long-term therapeutic effects that, in many patients with
CML, persist well beyond cessation of the treatment2830.
It is tempting to speculate that the characteristics of the
de Klein,A. etal. A cellular oncogene is translocated
to the Philadelphia chromosome in chronic myelocytic
leukaemia. Nature 300, 765767 (1982).
2. Deininger,M.W., Goldman,J.M. & Melo,J.V.
Themolecular biology of chronic myeloid leukemia.
Blood 96, 33433356 (2000).
3. Sawyers,C.L. Chronic myeloid leukemia.
N.Engl.J.Med. 340, 13301340 (1999).
4. Buchdunger,E. etal. Selective inhibition of the
platelet-derived growth factor signal transduction
pathway by a protein-tyrosine kinase inhibitor of the
2phenylaminopyrimidine class. Proc. Natl Acad. Sci.
USA 92, 25582562 (1995).
5. Druker,B.J. etal. Effects of a selective inhibitor of the
Abl tyrosine kinase on the growth of BcrAbl positive
cells. Nat. Med. 2, 561566 (1996).
6. Druker,B.J. & Lydon,N.B. Lessons learned from the
development of an Abl tyrosine kinase inhibitor for
chronic myelogenous leukemia. J.Clin. Invest. 105,
37 (2000).
7. Deininger,M.W., Goldman,J.M., Lydon,N.
& Melo,J.V. The tyrosine kinase inhibitor
CGP57148B selectively inhibits the growth of
BCRABL-positive cells. Blood 90, 36913698
(1997).
8. Druker,B.J. etal. Efficacy and safety of a specific
inhibitor of the BCRABL tyrosine kinase in chronic
myeloid leukemia. N.Engl. J.Med. 344, 10311037
(2001).
9. Abt,M.C. etal. Commensal bacteria calibrate the
activation threshold of innate antiviral immunity.
Immunity 37, 158170 (2012).
10. Druker,B.J. etal. Five-year followup of patients
receiving imatinib for chronic myeloid leukemia.
N.Engl. J.Med. 355, 24082417 (2006).
11. Hughes,T.P. etal. Long-term prognostic significance
of early molecular response to imatinib in newly
diagnosed chronic myeloid leukemia: an analysis from
the International Randomized Study of Interferon and
STI571 (IRIS). Blood 116, 37583765 (2010).
12. Kalmanti,L. etal. Safety and efficacy of imatinib in
CML over a period of 10years: data from the
randomized CML-study IV. Leukemia 29, 11231132
(2015).
13. van Oosterom,A.T. etal. Safety and efficacy of
imatinib (STI571) in metastatic gastrointestinal
stromal tumours: a phaseI study. Lancet 358,
14211423 (2001).
1.
disease have an important role in generating protective

long-term memory Tcells. In patients with GIST, NK cells
contribute to short-term and long-term adjuvant effects,
but might not coordinate adaptive immune responses
given the very rare percentages of complete responders
and the dependence upon imatinib administration, with
drug cessation leading to immediate relapse155. Half of the
patients with GIST present with an unfavourable NKp30
isoform phenotype that might account for the failure to
elicit antitumour Tcell responses. Specific therapeutic
interventions aimed at restoring NKp30 functions are
needed, such as compounds that modulate epigenetic
mechanisms, blockade of IL10, or neutralization of
soluble NKp30 ligands. In addition, imatinib-induced
immune resistance involves, at least partly, the domi
nance of TAM M2 macrophages that should be prevented
by interventions that interfere with the CSFR1 signalling
pathway (broad-spectrum, third-generation TKIs, or
antibodies and small molecules; TABLE1), or by the use
of drugs that kill these cells156,157. On the basis of these
considerations, it will be important to combine imatinib
with immunotherapeutic procedures to ameliorate the
treatment of GIST and CML. Moreover, the possibility
of using imatinib as a general immunostimulator for the
treatment of multiple distinct cancers, beyond its usual
indication that is restricted to GIST and CML, should be
actively explored.
14. Demetri,G.D. etal. Efficacy and safety of imatinib

mesylate in advanced gastrointestinal stromal tumors.
N.Engl. J.Med. 347, 472480 (2002).
15. Verweij,J. etal. Progression-free survival in
gastrointestinal stromal tumours with high-dose
imatinib: randomised trial. Lancet 364, 11271134
(2004).
16. Blanke,C.D. etal. Long-term results from a
randomized phaseII trial of standard- versus
higher-dose imatinib mesylate for patients with
unresectableor metastatic gastrointestinal stromal
tumors expressing KIT. J.Clin. Oncol. 26, 620625
(2008).
17. Blanke,C.D. etal. Phase III randomized, intergroup
trial assessing imatinib mesylate at two dose levels
inpatients with unresectable or metastatic
gastrointestinal stromal tumors expressing the kit
receptor tyrosine kinase: S0033. J.Clin. Oncol. 26,
626632 (2008).
18. Joensuu,H. etal. Effect of the tyrosine kinase inhibitor
STI571 in a patient with a metastatic gastrointestinal
stromal tumor. N.Engl. J.Med. 344, 10521056
(2001).
19. Thomas,A., Liu,S.V., Subramaniam,D.S.
& Giaccone,G. Refining the treatment of NSCLC
according to histological and molecular subtypes.
Nat.Rev. Clin. Oncol. 12, 511526 (2015).
20. Weisberg,E. & Griffin,J.D. Mechanism of resistance
to the ABL tyrosine kinase inhibitor STI571 in BCR/
ABL-transformed hematopoietic cell lines. Blood 95,
34983505 (2000).
21. Debiec-Rychter,M. etal. Mechanisms of resistance to
imatinib mesylate in gastrointestinal stromal tumors
and activity of the PKC412 inhibitor against imatinibresistant mutants. Gastroenterology 128, 270279
(2005).
22. Antonescu,C.R. etal. Acquired resistance to imatinib
in gastrointestinal stromal tumor occurs through
secondary gene mutation. Clin. Cancer Res. 11,
41824190 (2005).
23. Chen,L.L. etal. A missense mutation in KIT kinase
domain 1 correlates with imatinib resistance in
gastrointestinal stromal tumors. Cancer Res. 64,
59135919 (2004).
24. Gerlinger,M. etal. Intratumor heterogeneity and
branched evolution revealed by multiregion
sequencing. N.Engl. J.Med. 366, 883892
(2012).
25. Haber,D.A., Gray,N.S. & Baselga,J. The evolving

war on cancer. Cell 145, 1924 (2011).
26. Corbin,A.S. etal. Human chronic myeloid leukemia
stem cells are insensitive to imatinib despite inhibition
of BCRABL activity. J.Clin. Invest. 121, 396409
(2011).
27. Mahon,F.X. etal. Discontinuation of imatinib in
patients with chronic myeloid leukaemia who have
maintained complete molecular remission for at least
2years: the prospective, multicentre Stop Imatinib
(STIM) trial. Lancet Oncol. 11, 10291035 (2010).
28. Thielen,N. etal. Imatinib discontinuation in chronic
phase myeloid leukaemia patients in sustained
complete molecular response: a randomised trial of
the Dutch-Belgian Cooperative Trial for HaematoOncology (HOVON). Eur. J.Cancer 49, 32423246
(2013).
29. Shinohara,Y. etal. A multicenter clinical study
evaluating the confirmed complete molecular response
rate in imatinib-treated patients with chronic phase
chronic myeloid leukemia by using the international
scale of real-time quantitative polymerase chain
reaction. Haematologica 98, 14071413 (2013).
30. Ross,D.M. etal. Safety and efficacy of imatinib
cessation for CML patients with stable undetectable
minimal residual disease: results from the TWISTER
study. Blood 122, 515522 (2013).
31. Takahashi,N. etal. Discontinuation of imatinib in
Japanese patients with chronic myeloid leukemia.
Haematologica 97, 903906 (2012).
32. Vacchelli,E. etal. Trial watch: chemotherapy with
immunogenic cell death inducers. Oncoimmunology 3,
e27878 (2014).
33. Zitvogel,L., Galluzzi,L., Smyth,M.J. & Kroemer,G.
Mechanism of action of conventional and targeted
anticancer therapies: reinstating immunosurveillance.
Immunity 39, 7488 (2013).
34. Vanneman,M. & Dranoff,G. Combining
immunotherapy and targeted therapies in cancer
treatment. Nat. Rev. Cancer 12, 237251 (2012).
35. Druker,B.J. etal. Activity of a specific inhibitor of the
BCRABL tyrosine kinase in the blast crisis of chronic
myeloid leukemia and acute lymphoblastic leukemia
with the Philadelphia chromosome. N.Engl. J.Med.
344, 10381042 (2001).
36. Cohen,P.R. Sweets syndrome a comprehensive
review of an acute febrile neutrophilic dermatosis.
Orphanet J.Rare Dis. 2, 34 (2007).

.
d
e
v
r
e
s
e
r
s
t
h
g
i
r
l
l
A
.
d
e
t
i
m
i
L
s
r
e
h
s
i
l
b
u
P
n
a
l
l
i
m
c
a
M
6
1
0
2
REVIEWS
37. Shin,J.Y., Hu,W., Naramura,M. & Park,C.Y. High
cKit expression identifies hematopoietic stem cells
with impaired self-renewal and megakaryocytic bias.
J.Exp. Med. 211, 217231 (2014).
38. Bodine,D.M., Seidel,N.E., Zsebo,K.M. & Orlic,D.
Invivo administration of stem cell factor to mice
increases the absolute number of pluripotent
hematopoietic stem cells. Blood 82, 445455
(1993).
39. Thoren,L.A. etal. Kit regulates maintenance of
quiescent hematopoietic stem cells. J.Immunol. 180,
20452053 (2008).
40. Napier,R.J. etal. Low doses of imatinib induce
myelopoiesis and enhance host anti-microbial
immunity. PLoS Pathog. 11, e1004770 (2015).
41. Garcia,M. etal. Productive replication of Ebola virus
is regulated by the c-Abl1 tyrosine kinase. Sci. Transl.
Med. 4, 123ra24 (2012).
42. Swimm,A.I. etal. Abl family tyrosine kinases
regulate sialylated ganglioside receptors for
polyomavirus. J.Virol. 84, 42434251 (2010).
43. Wetzel,D.M., McMahon-Pratt,D. & Koleske,A.J.
The Abl and Arg kinases mediate distinct modes of
phagocytosis and are required for maximal
Leishmania infection. Mol. Cell. Biol. 32, 31763186
(2012).
44. Reeves,P.M. etal. Disabling poxvirus pathogenesis
by inhibition of Abl-family tyrosine kinases. Nat. Med.
11, 731739 (2005).
45. Sheng,Z., Ma,L., Sun,J.E., Zhu,L.J. & Green,M.R.
BCRABL suppresses autophagy through
ATF5mediated regulation of mTOR transcription.
Blood 118, 28402848 (2011).
46. Helgason,G.V., Karvela,M. & Holyoake,T.L. Kill one
bird with two stones: potential efficacy of BCRABL
and autophagy inhibition in CML. Blood 118,
20352043 (2011).
47. Appel,S. etal. Imatinib mesylate affects the
development and function of dendritic cells generated
from CD34+ peripheral blood progenitor cells. Blood
103, 538544 (2004).
48. Appel,S. etal. Effects of imatinib on monocytederived dendritic cells are mediated by inhibition
ofnuclear factor-B and Akt signaling pathways.
Clin.Cancer Res. 11, 19281940 (2005).
49. Taieb,J., Maruyama,K., Borg,C., Terme,M.
& Zitvogel,L. Imatinib mesylate impairs
Flt3Lmediated dendritic cell expansion and
antitumor effects invivo. Blood 103, 19661967;
author reply 1967 (2004).
50. Boissel,N. etal. Defective blood dendritic cells in
chronic myeloid leukemia correlate with high
plasmatic VEGF and are not normalized by imatinib
mesylate. Leukemia 18, 16561661 (2004).
51. van Dongen,M. etal. Anti-inflammatory M2 type
macrophages characterize metastasized and tyrosine
kinase inhibitor-treated gastrointestinal stromal
tumors. Int. J.Cancer 127, 899909 (2010).
52. Cavnar,M.J. etal. KIT oncogene inhibition drives
intratumoral macrophage M2 polarization.
J.Exp.Med. 210, 28732886 (2013).
53. Dietz,A.B. etal. Imatinib mesylate inhibits Tcell
proliferation invitro and delayed-type hypersensitivity
invivo. Blood 104, 10941099 (2004).
54. Seggewiss,R. etal. Imatinib inhibits Tcell receptormediated Tcell proliferation and activation in a dosedependent manner. Blood 105, 24732479 (2005).
55. Gao,H. etal. Imatinib mesylate suppresses cytokine
synthesis by activated CD4 Tcells of patients with
chronic myelogenous leukemia. Leukemia 19,
19051911 (2005).
56. de Lavallade,H. etal. Tyrosine kinase inhibitors
impair Bcell immune responses in CML through
off-target inhibition of kinases important for cell
signaling. Blood 122, 227238 (2013).
57. Steegmann,J.L. etal. Chronic myeloid leukemia
patients resistant to or intolerant of interferon alpha
and subsequently treated with imatinib show reduced
immunoglobulin levels and hypogammaglobulinemia.
Haematologica 88, 762768 (2003).
58. Cervetti,G. etal. Reduction of immunoglobulin levels
during imatinib therapy of chronic myeloid leukemia.
Leuk. Res. 32, 191192 (2008).
59. Carulli,G. etal. Reduced circulating Blymphocytes
and altered Bcell compartments in patients suffering
from chronic myeloid leukaemia undergoing therapy
with Imatinib. Hematol. Oncol. 33, 250252 (2014).
60. Carulli,G. etal. Abnormal phenotype of bone marrow
plasma cells in patients with chronic myeloid leukemia
undergoing therapy with Imatinib. Leuk. Res. 34,
13361339 (2010).
61. Arai,S. etal. A randomized phaseII crossover study of

imatinib or rituximab for cutaneous sclerosis after
hematopoietic cell transplantation. Clin. Cancer Res.
22, 319327 (2015).
62. Olivieri,A. etal. Long-term outcome and prospective
validation of NIH response criteria in 39 patients
receiving imatinib for steroid-refractory chronic GVHD.
Blood 122, 41114118 (2013).
63. Catellani,S., Pierri,I., Gobbi,M., Poggi,A.
& Zocchi,M.R. Imatinib treatment induces CD5+ B
lymphocytes and IgM natural antibodies with antileukemic reactivity in patients with chronic
myelogenous leukemia. PLoS ONE 6, e18925 (2011).
64. Oriss,T.B., Krishnamoorthy,N., Ray,P. & Ray,A.
Dendritic cell ckit signaling and adaptive immunity:
implications for the upper airways. Curr. Opin. Allergy
Clin. Immunol. 14, 712 (2014).
65. Aswald,J.M., Lipton,J.H., Aswald,S.
& Messner,H.A. Increased IFN- synthesis by Tcells
from patients on imatinib therapy for chronic myeloid
leukemia. Cytokines Cell. Mol. Ther. 7, 143149
(2002).
66. Chen,C.I., Maecker,H.T. & Lee,P.P. Development
and dynamics of robust Tcell responses to CML under
imatinib treatment. Blood 111, 53425349 (2008).
67. Riva,G. etal. Emergence of BCRABL-specific cytotoxic
Tcells in the bone marrow of patients with Ph+ acute
lymphoblastic leukemia during long-term imatinib
mesylate treatment. Blood 115, 15121518 (2010).
68. Riva,G. etal. Long-term molecular remission with
persistence of BCRABL1specific cytotoxic Tcells
following imatinib withdrawal in an elderly patient with
Philadelphia-positive ALL. Br. J.Haematol. 164,
299302 (2014).
69. Borg,C. etal. Novel mode of action of ckit tyrosine
kinase inhibitors leading to NK cell-dependent
antitumor effects. J.Clin. Invest. 114, 379388
(2004).
70. Menard,C. etal. Natural killer cell IFN- levels predict
long-term survival with imatinib mesylate therapy in
gastrointestinal stromal tumor-bearing patients.
Cancer Res. 69, 35633569 (2009).
71. Blay,J.Y. etal. Nilotinib versus imatinib as first-line
therapy for patients with unresectable or metastatic
gastrointestinal stromal tumours (ENESTg1): a
randomised phase 3 trial. Lancet Oncol. 16, 550560
(2015).
72. Sako,H. etal. Antitumor effect of the tyrosine kinase
inhibitor nilotinib on gastrointestinal stromal tumor
(GIST) and imatinib-resistant GIST cells. PLoS ONE 9,
e107613 (2014).
73. Kijima,M., Gardiol,N. & Held,W. Natural killer cell
mediated missing-self recognition can protect mice
from primary chronic myeloid leukemia invivo.
PLoSONE 6, e27639 (2011).
74. Binotto,G. etal. Comparative analysis of NK receptor
and Tcell receptor repertoires in patients with chronic
myeloid leukemia treated with different tyrosine incase
inhibitors. Blood 124, 5508 (2014).
75. Ohyashiki,K. etal. Increased natural killer cells and
decreased CD3+CD8+CD62L+ Tcells in CML patients
who sustained complete molecular remission after
discontinuation of imatinib. Br. J.Haematol. 157,
254256 (2012).
76. Ilander,M. M. etal. Early disease relapse after
tyrosine kinase inhibitor treatment discontinuation in
CML is related both to low number and impaired
function of NKcells. Blood 124, 812812 (2014).
77. Delphine Rea,N.D. etal. Low natural killer (NK) cell
counts and functionality are associated with molecular
relapse after imatinib discontinuation in patients (pts)
with chronic phase (CP)-chronic myeloid leukemia
(CML) with undetectable BCRABL transcripts for at
least 2 years: preliminary results from immunostim, on
behalf of STIM investigators. Blood 122, 856856
(2013).
78. Balachandran,V.P. etal. Imatinib potentiates
antitumor Tcell responses in gastrointestinal stromal
tumor through the inhibition of Ido. Nat. Med. 17,
10941100 (2011).
79. Larmonier,N. etal. Imatinib mesylate inhibits CD4+
CD25+ regulatory Tcell activity and enhances active
immunotherapy against BCRABL tumors.
J.Immunol. 181, 69556963 (2008).
80. Giallongo,C. etal. Myeloid derived suppressor cells
(MDSCs) are increased and exert immunosuppressive
activity together with polymorphonuclear leukocytes
(PMNs) in chronic myeloid leukemia patients.
PLoSONE 9, e101848 (2014).
81. Christiansson,L. etal. The tyrosine kinase inhibitors
imatinib and dasatinib reduce myeloid suppressor
cells and release effector lymphocyte responses.

Mol.Cancer Ther. 14, 11811191 (2015).
82. Christiansson,L. etal. Increased level of myeloidderived suppressor cells, programmed death receptor
ligand 1/programmed death receptor 1, and soluble
CD25 in Sokal high risk chronic myeloid leukemia.
PLoS ONE 8, e55818 (2013).
83. Rusakiewicz,S. etal. Immune infiltrates are prognostic
factors in localized gastrointestinal stromal tumors.
Cancer Res. 73, 34993510 (2013).
84. Barrett,A.J. & Ito,S. The role of stem cell
transplantation for chronic myelogenous leukemia
inthe 21st century. Blood 125, 32303235 (2015).
85. Drobyski,W.R. etal. Tcell depletion plus salvage
immunotherapy with donor leukocyte infusions as
astrategy to treat chronic-phase chronic
myelogenousleukemia patients undergoing HLAidentical sibling marrow transplantation. Blood 94,
434441 (1999).
86. Spierings,E. Minor histocompatibility antigens: past,
present, and future. Tissue Antigens 84, 374360
(2014).
87. Spierings,E. etal. Multicenter analyses demonstrate
significant clinical effects of minor histocompatibility
antigens on GvHD and GvL after HLA-matched related
and unrelated hematopoietic stem cell
transplantation. Biol. Blood Marrow Transplant. 19,
12441253 (2013).
88. Oostvogels,R. etal. Identification of minor
histocompatibility antigens based on the 1000
Genomes Project. Haematologica 99, 18541859
(2014).
89. Butt,N.M. etal. Circulating bcrabl-specific CD8+
Tcells in chronic myeloid leukemia patients and
healthy subjects. Haematologica 90, 13151323
(2005).
90. Bellantuono,I. etal. Two distinct HLAA0201
presented epitopes of the Wilms tumor antigen 1 can
function as targets for leukemia-reactive CTL. Blood
100, 38353837 (2002).
91. Knights,A.J. etal. A novel MHC-associated
proteinase 3 peptide isolated from primary chronic
myeloid leukaemia cells further supports the
significance of this antigen for the immunotherapy of
myeloid leukaemias. Leukemia 20, 10671072
(2006).
92. Luetkens,T. etal. Expression, epigenetic regulation,
and humoral immunogenicity of cancer-testis
antigensin chronic myeloid leukemia. Leuk. Res. 34,
16471655 (2010).
93. Quintarelli,C. etal. High-avidity cytotoxic T
lymphocytes specific for a new PRAME-derived
peptide can target leukemic and leukemic-precursor
cells. Blood 117, 33533362 (2011).
94. Quintarelli,C. etal. Cytotoxic T lymphocytes directed
to the preferentially expressed antigen of melanoma
(PRAME) target chronic myeloid leukemia. Blood 112,
18761885 (2008).
95. Adams,S.P. etal. Frequent expression of HAGE in
presentation chronic myeloid leukaemias. Leukemia
16, 22382242 (2002).
96. Roman-Gomez,J. etal. Epigenetic regulation of
human cancer/testis antigen gene, HAGE, in chronic
myeloid leukemia. Haematologica 92, 153162
(2007).
97. Yang,X.F. etal. CML28 is a broadly immunogenic
antigen, which is overexpressed in tumor cells.
CancerRes. 62, 55175522 (2002).
98. Yang,X.F. etal. CML66, a broadly immunogenic
tumor antigen, elicits a humoral immune response
associated with remission of chronic myelogenous
leukemia. Proc. Natl Acad. Sci. USA 98, 74927497
(2001).
99. Zhang,W. etal. Graft-versus-leukemia antigen CML66
elicits coordinated Bcell and Tcell immunity after
donor lymphocyte infusion. Clin. Cancer Res. 16,
27292739 (2010).
100. Lin,Y. etal. Effective posttransplant antitumor
immunity is associated with TLR-stimulating nucleic
acidimmunoglobulin complexes in humans.
J.Clin.Invest. 121, 15741584 (2011).
101. Delahaye,N.F. etal. Alternatively spliced NKp30
isoforms affect the prognosis of gastrointestinal
stromal tumors. Nat. Med. 17, 700707 (2011).
102. Pogge von Strandmann,E. etal. Human leukocyte
antigen-Bassociated transcript 3 is released from
tumor cells and engages the NKp30 receptor on
natural killer cells. Immunity 27, 965974 (2007).
103. Binici,J. & Koch,J. BAG6, a jack of all trades in
health and disease. Cell. Mol. Life Sci. 71,
18291837 (2014).
.
d
e
v
r
e
s
e
r
s
t
h
g
i
r
l
l
A
.
d
e
t
i
m
i
L
s
r
e
h
s
i
l
b
u
P
n
a
l
l
i
m
c
a
M
6
1
0
2
REVIEWS
104. Binici,J. etal. A soluble fragment of the tumor
antigen BCL2associated athanogene 6 (BAG6) is
essential and sufficient for inhibition of NKp30
receptor-dependent cytotoxicity of natural killer cells.
J.Biol. Chem. 288, 3429534303 (2013).
105. Reiners,K.S. etal. Soluble ligands for NK cell
receptors promote evasion of chronic lymphocytic
leukemia cells from NK cell anti-tumor activity. Blood
121, 36583665 (2013).
106. Brandt,C.S. etal. The B7 family member B7H6 is a
tumor cell ligand for the activating natural killer cell
receptor NKp30 in humans. J.Exp. Med. 206,
14951503 (2009).
107. Semeraro,M. etal. Clinical impact of the NKp30/
B7H6 axis in high-risk neuroblastoma patients.
Sci.Transl. Med. 7, 283ra55 (2015).
108. Voron,T. etal. VEGFA modulates expression of
inhibitory checkpoints on CD8+ Tcells in tumors.
J.Exp. Med. 212, 139148 (2015).
109. Terme,M., Tartour,E. & Taieb,J. VEGFA/VEGFR2targeted therapies prevent the VEGFA-induced
proliferation of regulatory Tcells in cancer.
Oncoimmunology 2, e25156 (2013).
110. Motz,G.T. etal. Tumor endothelium FasL establishes
a selective immune barrier promoting tolerance in
tumors. Nat. Med. 20, 607615 (2014).
111. Legros,L. etal. Imatinib mesylate (STI571) decreases
the vascular endothelial growth factor plasma
concentration in patients with chronic myeloid
leukemia. Blood 104, 495501 (2004).
112. Legros,L. etal. Interferon decreases VEGF levels in
patients with chronic myeloid leukemia treated with
imatinib. Leuk. Res. 38, 662665 (2014).
113. Gramza,A.W., Corless,C.L. & Heinrich,M.C.
Resistance to tyrosine kinase inhibitors in
gastrointestinal stromal tumors. Clin. Cancer Res. 15,
75107518 (2009).
114. Cioffi,A. & Maki,R.G.G.I. Stromal tumors: 15 years
of lessons from a rare cancer. J.Clin. Oncol. 33,
18491854 (2015).
115. Yhim,H.Y. etal. Imatinib mesylate discontinuation
inpatients with chronic myeloid leukemia who have
received front-line imatinib mesylate therapy and
achieved complete molecular response. Leuk. Res. 36,
689693 (2012).
116. Greiner,J. & Schmitt,M. Leukemia-associated
antigens as target structures for a specific
immunotherapy in chronic myeloid leukemia.
Eur.J.Haematol. 80, 461468 (2008).
117. Li,Y., Lin,C. & Schmidt,C.A. New insights into
antigen specific immunotherapy for chronic myeloid
leukemia. Cancer Cell. Int. 12, 52 (2012).
118. Cathcart,K. etal. A multivalent bcrabl fusion
peptidevaccination trial in patients with chronic
myeloid leukemia. Blood 103, 10371042 (2004).
119. Bocchia,M. etal. Effect of a p210 multipeptide
vaccine associated with imatinib or interferon in
patients with chronic myeloid leukaemia and
persistent residual disease: a multicentre
observational trial. Lancet 365, 657662 (2005).
120. Maisonneuve,C., Bertholet,S., Philpott,D.J. &
DeGregorio,E. Unleashing the potential of NODandToll-like agonists as vaccine adjuvants. Proc. Natl
Acad. Sci. USA 111, 1229412299 (2014).
121. Valmori,D. etal. Vaccination with NYESO1 protein
and CpG in Montanide induces integrated antibody/
Th1 responses and CD8 Tcells through crosspriming.Proc. Natl Acad. Sci. USA 104, 89478952
(2007).
122. Sabbatini,P. etal. Phase I trial of overlapping long
peptides from a tumor self-antigen and poly-ICLC
shows rapid induction of integrated immune response
in ovarian cancer patients. Clin. Cancer Res. 18,
64976508 (2012).
123. De Carvalho,D.D. etal. BCRABL-mediated
upregulation of PRAME is responsible for knocking
down TRAIL in CML patients. Oncogene 30,
223233 (2011).
124. Perez,D. etal. Cancer testis antigen expression in
gastrointestinal stromal tumors: new markers for
early recurrence. Int. J.Cancer 123, 15511555
(2008).
125. Perez,D. etal. Protein expression of cancer
testisantigens predicts tumor recurrence and
treatment response to imatinib in gastrointestinal
stromal tumors. Int. J.Cancer 128, 29472952
(2011).
126. Talpaz,M., Hehlmann,R., Quintas-Cardama,A.,
Mercer,J. & Cortes,J. Reemergence of interferon-
in the treatment of chronic myeloid leukemia.
Leukemia 27, 803812 (2013).
127. Preudhomme,C. etal. Imatinib plus peginterferon

alfa2a in chronic myeloid leukemia. N.Engl. J.Med.
363, 25112521 (2010).
128. Hehlmann,R. etal. Tolerability-adapted imatinib
800mg/d versus 400mg/d versus 400mg/d plus
interferon- in newly diagnosed chronic myeloid
leukemia. J.Clin. Oncol. 29, 16341642 (2011).
129. Guilhot,F.etal. Long term outcome of chronic
phasechronic myeloid leukemia (CP CML) patients
(pts) from the French Spirit Study comparing imatinib
(IM) 400mg to higher dose imatinib or combination
with peginterferon2a (PegIFN) or cytarabine
(AraC):atrial of the FI LMC (France intergroupe
delaleucemie mylode chronique). Blood 124,
17931793 (2014).
130. Stagno,F., Vigneri,P. & Di Raimondo,F. Clinical
relevance of the association of interferon alfa to
imatinib in chronic myeloid leukemia therapy.
Int.J.Hematol. 96, 142143 (2012).
131. Burchert,A. etal. Sustained molecular response with
interferon alfa maintenance after induction therapy
with imatinib plus interferon alfa in patients with
chronic myeloid leukemia. J.Clin. Oncol. 28,
14291435 (2010).
132. Chen,L.L. etal. Exploiting antitumor immunity to
overcome relapse and improve remission duration.
Cancer Immunol. Immunother. 61, 11131124
(2012).
133. Taieb,J. etal. A novel dendritic cell subset involved in
tumor immunosurveillance. Nat. Med. 12, 214219
(2006).
134. Chan,C.W. etal. Interferon-producing killer
dendriticcells provide a link between innate and
adaptive immunity. Nat. Med. 12, 207213
(2006).
135. Zitvogel,L. & Housseau,F. IKDCs or B220+
NKcellsare pre-mNK cells. Blood 119, 43454346
(2012).
136. Guimont-Desrochers,F. etal. Redefining interferonproducing killer dendritic cells as a novel intermediate
in NKcell differentiation. Blood 119, 43494357
(2012).
137. Ullrich,E. etal. Trans-presentation of IL15 dictates
IFN-producing killer dendritic cells effector functions.
J.Immunol. 180, 78877897 (2008).
138. Terme,M. etal. The dendritic cell-like functions of IFNproducing killer dendritic cells reside in the CD11b+
subset and are licensed by tumor cells. Cancer Res.
69, 65906597 (2009).
139. Himoudi,N. etal. Migratory and antigen presentation
functions of IFN-producing killer dendritic cells.
CancerRes. 69, 65986606 (2009).
140. Pautier,P. etal. Phase I clinical trial combining
imatinib mesylate and IL2 in refractory cancer
patients: IL2 interferes with the pharmacokinetics
ofimatinib mesylate. Oncoimmunology 2, e23079
(2013).
141. Chaput,N. etal. Phase I clinical trial combining
imatinib mesylate and IL2: HLADR NK cell levels
correlate with disease outcome. Oncoimmunology 2,
e23080 (2013).
142. Melki,I. & Crow,Y.J. Novel monogenic diseases
causing human autoimmunity. Curr. Opin. Immunol.
37, 15 (2015).
143. Sharma,P. & Allison,J.P. Immune checkpoint
targeting in cancer therapy: toward combination
strategies with curative potential. Cell 161, 205214
(2015).
144. Topalian,S.L., Drake,C.G. & Pardoll,D.M. Immune
checkpoint blockade: a common denominator
approach to cancer therapy. Cancer Cell 27, 450461
(2015).
145. Mumprecht,S., Schurch,C., Schwaller,J.,
Solenthaler,M. & Ochsenbein,A.F. Programmed
death 1 signaling on chronic myeloid leukemia-specific
Tcells results in Tcell exhaustion and disease
progression. Blood 114, 15281536 (2009).
146. US National Library of Science. ClinicalTrials.gov
[online], https://clinicaltrials.gov/ct2/show/
NCT02011945 (2016).
147. Holmgaard,R.B., Zamarin,D., Munn,D.H.,
Wolchok,J.D. & Allison,J.P. Indoleamine
2,3dioxygenase is a critical resistance mechanism
inantitumor Tcell immunotherapy targeting CTLA4.
J.Exp. Med. 210, 13891402 (2013).
NCT01643278 (2016).
NCT01738139 (2016).
150. Wu,M.R. etal. B7H6specific bispecific T cell engagers

lead to tumor elimination and host antitumor
immunity. J.Immunol. 194, 53055311 (2015).
151. Zhang,T., Wu,M.R. & Sentman,C.L. An NKp30
based chimeric antigen receptor promotes Tcell
effector functions and antitumor efficacy invivo.
J.Immunol. 189, 22902299 (2012).
152. Wu,M.R., Zhang,T., DeMars,L.R. & Sentman,C.L.
B7H6specific chimeric antigen receptors lead to
tumor elimination and host antitumor immunity.
GeneTher. 22, 675684 (2015).
153. Rohon,P., Porkka,K. & Mustjoki,S. Immunoprofiling
of patients with chronic myeloid leukemia at
diagnosisand during tyrosine kinase inhibitor therapy.
Eur. J.Haematol. 85, 387398 (2010).
154. HuLieskovan,S., Robert,L., Homet Moreno,B.
& Ribas,A. Combining targeted therapy with
immunotherapy in BRAF-mutant melanoma: promise
and challenges. J.Clin. Oncol. 32, 22482254
(2014).
155. Le Cesne,A. etal. Discontinuation of imatinib in
patients with advanced gastrointestinal stromal
tumours after 3years of treatment: an open-label
multicentre randomised phase 3 trial. Lancet Oncol.
11, 942949 (2010).
156. Allavena,P., Germano,G., Belgiovine,C., DIncalci,M.
& Mantovani,A. Trabectedin: a drug from the sea that
strikes tumor-associated macrophages.
157. Germano,G. etal. Role of macrophage targeting in
the antitumor activity of trabectedin. Cancer Cell 23,
249262 (2013).
158. Bolen,J.B. & Brugge,J.S. Leukocyte protein
tyrosinekinases: potential targets for drug discovery.
Annu. Rev. Immunol. 15, 371404 (1997).
159. Gu,J.J., Ryu,J.R. & Pendergast,A.M. Abl tyrosine
kinases in Tcell signaling. Immunol. Rev. 228,
170183 (2009).
160. Fabian,M.A. etal. A small molecule-kinase
interaction map for clinical kinase inhibitors.
Nat.Biotechnol. 23, 329336 (2005).
161. Lee,K.C. etal. Lck is a key target of imatinib and
dasatinib in Tcell activation. Leukemia 24, 896900
(2010).
162. Dewar,A.L. etal. Macrophage colony-stimulating
factor receptor cfms is a novel target of imatinib.
Blood 105, 31273132 (2005).
163. Crittenden,M.R. etal. The peripheral myeloid
expansion driven by murine cancer progression is
reversed by radiation therapy of the tumor. PLoS ONE
8, e69527 (2013).
164. Kroemer,G., Galluzzi,L., Kepp,O. & Zitvogel,L.
Immunogenic cell death in cancer therapy. Annu. Rev.
Immunol. 31, 5172 (2013).
165. Garg,A.K. etal. Phase1/2 trial of single-session
stereotactic body radiotherapy for previously
unirradiated spinal metastases. Cancer 118,
50695077 (2012).
166. Gupta,A. etal. Autophagy inhibition and antimalarials
promote cell death in gastrointestinal stromal tumor
(GIST). Proc. Natl Acad. Sci. USA 107, 1433314338
(2010).
167. Ma,Y., Galluzzi,L., Zitvogel,L. & Kroemer,G.
Autophagy and cellular immune responses. Immunity
39, 211227 (2013).
168. Rao,S. etal. A dual role for autophagy in a murine
model of lung cancer. Nat. Commun. 5, 3056 (2014).
169. Okada,M. etal. A novel mechanism for imatinib
mesylate-induced cell death of BCRABL-positive
human leukemic cells: caspase-independent, necrosislike programmed cell death mediated by serine
protease activity. Blood 103, 22992307 (2004).
170. Green,D.R., Ferguson,T., Zitvogel,L. & Kroemer,G.
Immunogenic and tolerogenic cell death. Nat. Rev.
Immunol. 9, 353363 (2009).
171. Hirota,S. etal. Gainoffunction mutations of ckit in
human gastrointestinal stromal tumors. Science 279,
577580 (1998).
172. Heinrich,M.C., Blanke,C.D., Druker,B.J.
& Corless,C.L. Inhibition of KIT tyrosine kinase
activity: a novel molecular approach to the treatment
of KIT-positive malignancies. J.Clin. Oncol. 20,
16921703 (2002).
173. Sato,N. etal. The effects of STI571 on antigen
presentation of dendritic cells generated from patients
with chronic myelogenous leukemia. Hematol. Oncol.
21, 6775 (2003).
174. Wang,H. etal. Imatinib mesylate (STI571) enhances
antigen-presenting cell function and overcomes tumorinduced CD4+ Tcell tolerance. Blood 105, 11351143
(2005).

.
d
e
v
r
e
s
e
r
s
t
h
g
i
r
l
l
A
.
d
e
t
i
m
i
L
s
r
e
h
s
i
l
b
u
P
n
a
l
l
i
m
c
a
M
6
1
0
2
REVIEWS
175. Sinai,P. etal. Imatinib mesylate inhibits antigenspecific memory CD8 Tcell responses invivo.
J.Immunol. 178, 20282037 (2007).
176. Mumprecht,S., Matter,M., Pavelic,V.
& Ochsenbein,A.F. Imatinib mesylate selectively
impairs expansion of memory cytotoxic Tcells
withoutaffecting the control of primary viral
infections.Blood 108, 34063413 (2006).
177. Wei,J. etal. Nilotinib is more potent than imatinib
fortreating plexiform neurofibroma invitro and
invivo. PLoS ONE 9, e107760 (2014).
178. Kim,T.S. etal. Increased KIT inhibition enhances
therapeutic efficacy in gastrointestinal stromal
tumor.Clin. Cancer Res. 20, 23502362 (2014).
179. Mohty,M. etal. Imatinib and plasmacytoid
dendriticcell function in patients with chronic
myeloidleukemia. Blood 103, 46664668
(2004).
180. Kreutzman,A., Ilander,M., Porkka,K., Vakkila,J.

& Mustjoki,S. Dasatinib promotes Th1type
responses in granzyme B expressing Tcells.
181. Usuki,K. etal. CD8+ memory Tcells predominate
over nave Tcells in therapy-free CML patients with
sustained major molecular response. Leuk. Res. 33,
e164165 (2009).
Acknowledgements
L.Z. and G.K. are supported by the Institut National Du

Cancer (INCA), the Ligue contre le Cancer (quipe labellise);
Agence National de la Recherche (ANR) Projets blancs;
ANR under the frame of ERare2, the ERA-Net for Research
on Rare Diseases; Association pour la recherche sur le cancer
(ARC); Cancrople IledeFrance; Institut National du Cancer
(INCa); Institut Universitaire de France; Fondation pour la
Recherche Mdicale (FRM); the European Commission
(ArtForce); the European Research Council (ERC); the LabEx

Immuno-Oncology; the SIRIC Stratified Oncology Cell DNA
Repair and Tumour Immune Elimination (SOCRATE); the
SIRIC Cancer Research and Personalized Medicine (CARPEM);
and the Paris Alliance of Cancer Research Institutes (PACRI).
L.Z. is also supported by the Swiss Institute for Experimental
Cancer Research (ISREC) and the Swiss Bridge Foundation.
MA is supported by the Cancer Research Institute (CRI) and
the Ludwig Institute for Cancer Research (LICR).
Author contributions
All authors contributed to researching the data for the article

and to discussion of the content. L.Z., M.A. and G.K. contributed to the writing of the article, and all authors reviewed
and/or edited the manuscript before submission.
Competing interests statement
The authors declare no competing interests.
.
d
e
v
r
e
s
e
r
s
t
h
g
i
r
l
l
A
.
d
e
t
i
m
i
L
s
r
e
h
s
i
l
b
u
P
n
a
l
l
i
m
c
a
M
6
1
0
2

Immunological Off-Target Effects of Imatinib

Загружено:

Сведения о документе

Исходное описание:

Оригинальное название

Авторское право

Доступные форматы

Поделиться этим документом

Поделиться или встроить документ

Параметры публикации

Этот документ был вам полезен?

Это неприемлемый материал?

Авторское право:

Доступные форматы

Immunological Off-Target Effects of Imatinib

Загружено:

Авторское право:

Доступные форматы

REVIEWS

Immunological off-target effects

Gustave Roussy Cancer

Imatinib mesylate (Gleevec or Glivec, Novartis,

2phenylaminopyrimidine class4, and later on, more-

NATURE REVIEWS | CLINICAL ONCOLOGY

ADVANCE ONLINE PUBLICATION | 1

the safety and efficacy of imatinib in CML was confirmed

response lasting 2years. These results were further

Effects of imatinib on haematopoiesis

2 | ADVANCE ONLINE PUBLICATION

b The history of the rst TKI in GIST

May 2001: FDA

November 2001: approval in

Glivec given tradename

February 2002: FDA

June 2002: EMEA

efficient in priming of cytotoxic Tcell lymphocytes

and activation invitro, as well as delayed-type hyper

NATURE REVIEWS | CLINICAL ONCOLOGY

ADVANCE ONLINE PUBLICATION | 3

Favourable immune outcomes of imatinib

and the activation of splenic NK cells in mice69 (FIG.2).

4 | ADVANCE ONLINE PUBLICATION

Immune predictors of imatinib response

MHC classI molecules from GIST cells (which might

Table 1 | Off-target immunological effects of imatinib in preclinical models

After incubation with imatinib,

Enhanced ability for antigen

BMderived DCs from

BALB/c mice: invitro

TREG cell and FoxP3 expression

TREG-cell TCR signalling

Listeria monocytogenesOVA-based vaccine

Loss of OVA-specific TgTCR

Loss of IL7R on CD8+ Tcells

LCMV vaccine with LCMV

Effector antiviral Tcells and

Loss of memory Tcell

Athymic nu/nu mice

Antitumour effects of imatinib

Off-target effect greater with

B16F10, AK7, RMAS

DCNKcell cross talk

Kit signalling in DCs induced

TRAIL proficient versus

IKDC accumulation in tumour

Role of IL15 and NKG2D

GIST-bearing mice crossed

Imatinib polarized TAMs to

Imatinib versus CSF1R

Wild-type mice and

No effect of the combination

Prophylactic and for

Positive role of effector TC1

TREG-cell apoptosis in tumour

NATURE REVIEWS | CLINICAL ONCOLOGY

ADVANCE ONLINE PUBLICATION | 5

Table 2 |Off-target immunological effects of imatinib observed in clinical trials

NK cell IFN secretion levels after

DCLPS exvivo stimulation of

Imatinib versus nilotinib