TUMOR IMMUNOLOGY

Syarifuddin Wahid

GAMBARAN UMUM RESPON IMUN THD TUMOR

Sel tumor mengekspressikan antigen yang dikenal sebagai asing oleh sistem imun pejamu.(tumor antigen) Sayangnya respon imun pejamu kebanyakan gagal mencegah pertumbuhan tumor.(mekanisme ?) Tetapi respon imun dapat dipicu untuk efektif membunuh sel tumor. (immunotherapy)

TUMOR ANTIGENS
NORMAL DNA RNA SELF PRDUCTS: Protein,hydrocarbon,lipid (NORMAL PRODUCTS).

DNA MUTATION

RNA

FOREIGN OR SELF PRODUCTS.

(ABNORMAL PRODUCTS)

CARCINOGEN

TUMOR ANTIGENS

TUMOR ANTIGENS
Karena berasal dari sel normal, apakah sel tumor antigen. Kalau ya, apakah antigen itu dapat memicu respon imun ? Kalau ya, apakah respon imun itu cukup kuat mengeliminasi sel tumor ? Respon imun apa saja yang terlibat terhadap antigen tumor ?

1.Product of mutated oncogenes and tumor suppressor genes

Cell Membrane Tumor Antigens which related to carcinogenesis.
Ras

Carcinogen

Oncogens & Tumor Supp Genes (mutation)

Myc p53,

2.Product of other mutated genes

Cell Membrane Tumor antigens which not related to carcinogenesis
TSTAs

Carcinogen

Other genes (random mutation)

3.Abberantly Expressed Normal Cellular Genes

Cell Membrane Tumor antigens (Normal protein but inappropriate expression)
Tyrosinase MAGE

Gene Mutations Carcinogen

4.Tumor Antigens Encoded by Genome of Oncogenic Viruses

Cell Membrane Tumor antigens (Foreign antigens)
EBNAs(6) LMPs(2)

Oncogenic Viruses (EBV,HPV)

Viral Genes

VCAs

5.Oncofetal Antigens
Tumor antigens:
Normal protein in high level during development (fetal) AFP

Cell Membrane

Carcinogen

Silenced Normal Genes

CEA

6.Altered Glycoprotein & Glycolipid Antigens.

Tumor Antigens:
abnormal form of GP & GL and/or higher than normal level. GM2,GD2&GD3 CA-125,CA-19-9

Cell Membrane

Genes mutations Carcinogen

MUC-1

7.Tissue Spesific Differentiation Antigens

Tumor Antigen: Cell Membrane
normally produced by differentited cells

CD-10(CALLA) CD-20

Normal Genes Carcinogen

TUMOR ANTIGENS
Carsinogen treatment
genetic alterations ( gene amplification,deletian & translocation) expression of altered protein,glycoprotein & glycolipid (antigen) in tumor cells.

TUMOR ANTIGENS
1. Antigen yang ada pada sel tumor, dikenal oleh sistem imun pejamu sehingga memicu terjadinya respon imun (Makrogaphage, NK Cells, Antibody and Tcells). Yang dapat mengeliminasi/membunuh sel tumor(Immunosurveilance theory)

TUMOR ANTIGENS
Immune responses

Mcell

NKcell

Tcell

AB

antigen

antigen

TUMOR CELLS

TUMOR ANTIGENS
2. Antigen yang ada pada sel tumor (produk normal) tidak dikenal sebagai asing oleh tubuh tidak menimbul respon imun pada pejamu. Karena produk itu spesifik sel bersangkutan dipakai sebagai antigen untuk dibuatkan antibodinya pada binatang akan digunakan melacak antigen spesifik tsb (cari sel tumor) utk keperluan diagnose dan terapi

TUMOR ANTIGENS
ANIMAL Antigen Antibody

Diagnose & Therapy

TUMOR CELLS

Function of Tumor Antigens

Antigens Immune Respone Diagnose Therapy

1. Product of mutated oncogenes and tumor suppressor genes. 2. Product of other mutated genes 3. Abberantly expressed normal cellular proteins. 4. Tumor antigens encoded by genomes of oncogenic viruses. 5. Oncofetal Antigens. 6. Altered glycolipid and Glycoprotein Antigens 7. Tissue Spesific Differentiation Antigens.

Yes
Yes Yes Yes No

Yes
No Yes Yes Yes

Yes No Yes Yes No

Yes
No

Yes
Yes

Yes
Yes

IMMUNE RESPONSE TO TOMOR

1. Macrophage
2. Natural Kiler (NK) Cell .
3. Cytolytic T Lymphocyte

4. Helper T Lymphocyte
5. Antibody

Macrophage
1. Phagocytosis
Lysozymes

Lysis of tumor cells

Tumor cells Macrophage Tumor cells

2. Production of Cytokine TNF(Tumor Necrocis Factor).

A.
Tumor Cell

B.
RA TNF

TNF

Thrombosis intravasculer Necroses of Tumor Cells

Apoptosis of tumor cells

Cytolytic T Lymphocyte
A. Introduction of antitumor T cell response
Costimulator
Macrophage (APC) MHC-I TCR

T Lymp (CD-8)

Tumor Antigens

B. Effector phase of antitumor CTL response.

Tumor Cells
MHC-I Lysis of Tumor Cells Tumor Antigens TCR

Differentiation

CTL (CD-8)

Helper T Lymphocyte
Costimulator Macrophage (APC) MHC-II Tumor Antigens Helper T Lymp (CD-4) TCR

Production of Interferon-gamma Activation of Macrophage and NK Cells.

Activation of CTL

Production of TNF

Lysis of Tumor Cells

Apoptosis of Tumor Cells

Necroses of Tumor Cells

Natural Killer (NK) Cells

= tumor antigen
NK Cells

No expression of MHC-I

Adhesion molecules

Tumor cells

Cytokines (IL-1,IL-12,INF-G)
NK Cells

Lysis of tumor cells

FcRes IgG
Tumor cells

(ADCC)

IgG antibody-coated tumor cells

ANTIBODY
= tumor antigen
antibody-coated tumor cells

ComIgG or IgM plement

Tumor cells

Lysis of tumor cells

NK cells/ FcRes IgG ADCC Macrophages
Tumor cells

IgG antibody-coated tumor cells

EVASION OF IMMUNE RESPONSES BY TUMORS

1. Class I MHC expression may be downregulated on tumor cells..

Tumor Cells MHC-I Lysis of Tumor Cells Tumor Antigens TCR

CTL (CD-8)

Tumor Cells TCR No Lysis of Tumor Cells No expression of Tumor Antigens

CTL (CD-8)

2. Tumors lose expression of antigens that elicit immune responses

Immune responses

Mcell

NKcell

Tcell

AB

antigen

? Lose expression
of antigen

TUMOR CELLS

3. No expression of MHC-II or costimulator

Costimulator Macrophage (APC) MHC-II Tumor Antigens Helper T Lymp (CD-4)

TCR

Production of Interferon-gamma Activation of Macrophages and NK Cells.

Activation of CTL

Production of TNF

Lysis of Tumor Cells

Apoptosis of Tumor Cells

Necroses of Tumor Cells

4. The produce of tumor may suppress antitumor immune response.

Costimulator
Macrophage (APC) MHC-I TCR

TGF-B
T Lymp (CD-8)

TGF-B
Tumor Antigens

B. Effector phase of antitumor CTL response.

Differentiation

TGF-B
Lysis of Tumor Cells

Tumor Cells
MHC-I Tumor Antigens TCR

CTL (CD-8)

5. Tumor antigens may induce specific immunologic tolerance.

Immune responses

Mcell

NKcell

Tcell

AB

antigen

antigen

TUMOR CELLS

6. The Cell surface antigens of tumors may be hidden from the immune system
(antigen masking, fibrin cocoon & antigenantibody complexs)
Immune responses

Mcell

NKcell

Tcell

AB

antigen

TUMOR CELLS

IMMUNOTHERAPY FOR TUMORS

1.STIMULATION OF ACTIVE HOST IMMUNE RESPONSE TO TUMORS

.
A. VACCINATION WITH TUMOR CELLS AND TUMOR ANTIGENS B. AUGMENTATION OF HOST IMMUNITY TO TUMORS WITH CYTOKINES AND COSTIMULATORS (IL-2, IL-4, INF-Gamma, GMCSF and B-7) C. NONSPECIFIC STIMULATION OF THE IMMUNE SYSTEM ADMINISTRATION OF POLYCLONAL ACTIVATORS OF LYMPHOCYTES. (BCG, ANTI-CD3 ANTIBODY).

Vaccination with tumor cells or tumor antigens

(Therapoitic Vaccine)
Host

Host
Purifed antigen + adjuvants CTL Plasmid (cDNA) or gene encoding tumor antigen. APC (professional) APC

Purifed antigen

Lysis of tumor cells

Basic Principles of therapoitic vaccine

1. Applied on tumor bearing individual (Patient) 2. Inducing immune respon by improving the ability of host immune system to recognise the tumor antigen. 3. The best vaccine material is purified tumor antigen which will stimulate the activation of CTL.

4. Professional APC (Dendritic Cells) recognise tumor antigens in vitro and then stimulate CTL in tumor bearing individual

Vaccination with tumor cells or tumor antigens

1. Antigen produced by random mutation in
cellular genes impractical for vaccination. 2. Tumor antigens shared by many tumors : MAGE, tyrosinase,gp100 (Melanoma) Ras dan p53 (many tumors) potentially useful immunogens. 3. Preventive vaccination by virus antigen (HBV)

Vaccine Materials
1. Killed tumor cells. 2. Purified tumor antigen 3.Dendritic Cells pulsed with tumor antigen (Professional APC) 4. Plasmid DNA

5. Dendritic cells with plasmid expresing tumor antigen (professional APC)

Augmentation of host immunity to tumors with cytokines and costimulators

(IL-2, IL-4, INF-Gamma, GMCSF and B-7)
Costimulator Tumor Cells MHC-I Tumor Antigens B7 Costimulator Tumor Cells MHC-I TCR TCR

T Lymp (CD-8)

T Lymp (CD-8)

Tumor Antigens
Transfected with gene for B7 Activation of tumor specific T cells.(CTL)

Augmentation of host immunity to tumors with cytokines and costimulators

(IL-2, IL-4, INF-Gamma, GMCSF and B-7)

Transfected with gene for IL-2

B7 Costimulator Tumor Cells

Activation of tumor specific T cells.(CTL)

MHC-I
Tumor Antigens IL-2

TCR

T Lymp (CD-8)

Nonspecific Stimulation of the immune system by administration of polyclonal activators of lymphocytes

TBC ACTIVATION OF LYMPOCYTES (POLYCLONAL)

BCG

PENYAKIT LAIN

TUMOR

IMMUNOTHERAPY FOR TUMORS

2. PASSIVE IMMUNOTHERAPY FOR TUMORS WITH T CELLS AND ANTIBODY

A. ADOPTIVE CELLULAR THERAPY B. THERAPY WITH ANTITUMOR ANTIBODIES

Adoptive cellular therapy

Host
CTL
CTL CTL CTL CTL CTL CTL

IL-2

Host
CTL

CTL CTL

CULTURE

Lysis of tumor cells

Lysis of tumor cells

Therapy with antitumor antibody

Antigen

ANIMAL Antibody Monoclonal

Toxix molecule, drug, radioisotop

TUMOR CELLS

SUMMARY
1. TUMORS
ANTIGENS IMMUNE RESPONSE 2. CTLs ARE THE PRINCIPAL OF ANTITUMOR IMMUNITY. 3. ANTIBODIES SPESIFIC FOR TUMOR FOR DIAGNOSIS & THERAPY

SUMMARY
4. IMMUNE RESPONSE FOR KILLING TUMOR : CTLs, NK CELLS & ACTIVATED MACROPHAGE 5. TUMOR MAY EVADE IMMUNE RESPONSE. 6. IMMUNOTHERAPY A. TO AUGMENT ACTIVE IMMUNE RESPONSE B. PASSIVE IMMUNOTHERAPY

TERIMA KASIH