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CAPR-14-0314
Cancer
Prevention
Research
Abstract
Prophylactic vaccines have been a major advance in preventing the development of infections after exposure to pathogens. When contemplating an effective approach to cancer
prevention, vaccines offer unique advantages over other more
standard approaches: First, once appropriately stimulated,
antigen-specic T cells will travel to all sites of disease and
eradicate cells bearing the proteins to which the T cells have
been primed by vaccination. Second, successful immunization
will further result in the development of immunologic memory, providing lifelong immunologic surveillance. There is
evidence of an adaptive tumor immune inltrate even at the
earliest stages of breast and colon cancer development. Furthermore, there is measurable immunity to lesion-associated
antigens present in patients who will eventually develop
malignancy even before cancer is clinically evident. Recent
studies are beginning to unmask the preinvasive antigenic
repertoire for these two malignancies. Preliminary experiments in transgenic mouse models of mammary and intestinal
tumors suggest that immunization against antigens expressed
in preinvasive and high-risk lesions may be effective in preventing the development of invasive malignancy. Cancer Prev
Introduction
Prophylactic vaccines that target pathogens, which cause signicant human morbidity and mortality, has been one of the
most successful interventions used in humans to prevent disease.
In the United States alone, there has been a 99% decrease in the
incidence of infectious diseases that are targeted by common
childhood vaccinations (1). The success of vaccines in the prevention of infectious disease has resulted in exploring immunetargeting approaches for the prevention and/or treatment of a
variety of non-infectious diseases, such as Alzheimer disease,
atherosclerosis, cancer, and even nicotine addiction (24). To be
effective, vaccines must arm the immune system to destroy the
cause of disease. In an infection, the pathogen has been dened,
but in malignancy the initiating abnormality is generally
unknown. Although the specic cause of a cancer may be multifactorial, there are a limited number of genetic alterations that
will stimulate the initiation and maintenance of the malignancy.
If we could dene the antigenic repertoire of preinvasive high-risk
lesions, perhaps the immune system could be armed via vaccination to eradicate cells expressing those proteins to prevent the
development of cancer.
Recent evidence indicates that type I immunity, associated with
the production of IFNg, is needed for cancer eradication. Type I
immunity enhances cross-priming at the site of cancer initiation
by activating local antigen-presenting cells (APC) to more ef-
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Figure 1.
Evolution of adaptive immunity
during breast cancer progression.
As breast cells develop progressive
atypia and then invasion of the
basement membrane (pink circle) in
invasive carcinoma, the adaptive
immune response also increases.
Immune inltrate is graded from 0
(no inltrate), (low inltrate),
(intermediate inltrate), (high
inltrate), to (very high
inltrate).
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Marquez et al.
Figure 2.
Evolution of adaptive immunity
during colon cancer progression. As
the epithelial cells of the colonic
lumen develop atypia and then
invade the basement membrane
(pink bar), adaptive immunity is
regulated. Immune inltrate is
graded from 0 (no inltrate), (low
inltrate), (intermediate
inltrate), (high inltrate), to
(very high inltrate).
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Conclusions
The importance of the preexisting immune response has
emerged in both colon and breast cancers, and there is further
evidence that the immune response to the atypical cells begins
in preinvasive disease (16, 29). Autoantibodies present in
patients that will develop colon or breast cancer but not in
normal controls suggest that the immune system is able to
recognize the preinvasive lesions. However, evidence of immunosuppressive inltrate predicting worse outcome in preinvasive lesions suggests that, similar to invasive lesions, preinvasive tumors are able to escape the immune system. Priming the
immune system to recognize and destroy cancer as it develops
has distinct advantages over more classic forms of chemoprevention. One advantage is that exposure to antigen to stimulate
T cells can occur over a short period of time, yet immunologic
memory generated from this exposure can last a lifetime. Also,
T cells will travel to any site in the body where cancer occurs and
eliminate cells that have begun to express the aberrant protein
against which the T cell was primed. Finally, immune therapies
have been shown to be generally well tolerated with minimal
side effects, which is critical in preventative vaccines that will be
given to otherwise healthy high-risk patients. One key to
effective vaccines for cancer prevention is the identication of
the preinvasive antigenic repertoire that will provide the targets
for active immunization.
Grant Support
M.L. Disis is supported by NCI U01 CA141539, DOD grant W81XWH-111-0760, and NCI contract N01-CN-53300/WA#10, as well as the Athena
Distinguished Professorship of Breast Cancer Research, and is a Komen
Foundation Scholar. S.E. Stanton is supported by the NIH T32 CA00951528. J.P. Marquez is supported by the Saide Marcos Foundation and Centro de
Investigacion de Cancer en Sonora, IAP (CICS) by Lic. Jose German Coppel
Luken Fund.
Received September 22, 2014; revised December 15, 2014; accepted
December 28, 2014; published OnlineFirst January 8, 2015.
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Marquez et al.
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