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TUMOR IMMUNOLOGY

TUMOR IMMUNOLOGY. Cancer is a result of multiple mutations. MORE THAN 100 VARIOUS TUMOR TYPES MULTISTEP TUMORIGENESIS DYNAMIC CHANGE OF TUMOR GENOME Genetic instability Oncogenes – ‘ gain of function ’ change Tumor suppressor genes – recessive ‘ loss of function ’ change

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TUMOR IMMUNOLOGY

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  1. TUMOR IMMUNOLOGY

  2. Cancer is a result of multiple mutations • MORE THAN 100 VARIOUS TUMOR TYPES • MULTISTEP TUMORIGENESIS • DYNAMIC CHANGE OF TUMOR GENOME • Genetic instability • Oncogenes – ‘gain of function’ change • Tumor suppressor genes – recessive ‘loss of function’ change • PROGRESSIVE TRANSFORMATION • Benign tumor abnormal, but limited growth • Malignant tumor unlimited growth, break basal membranes, invasion • Metastatic tumor seeds new tumors at distant sites. • MULTIPLE LIMITING AND INHIBITORY CHECK POINTS • Growth advantage • Selection • REGULATORY CIRCUITS • Inherent cell autonomous regulatory mechanisms • Microenvironmental factors INDEPENDENT OF THE IMMUNE SYSTEM

  3. Benign or malignant tumors

  4. ACTIVATION OF ONCOGENES Mitogens Growth factor receptors Secondary messengers Tarnscriptional activators Cell cycle genes Malignant cell INACTIVATION OF TUMOR SUPPRESSOR GENES Growth inhibitors Cell cycle inhibitors Programmed cell death genes DNA repair enzymes Tumor stem cell ACQUIRED PROPERTIES Independent growth factor signals Resistance to growth inhibitory factors Avoid apoptosis Unlimited proliferation Sustained angiogenesis Tissue migration and metastasis Malignant transformation Tissue cell Hanahan D és Weinberg RA 2000 Cell

  5. Reaction of the immune system TOLERANCE RECOGNITION Tumor antigens Common TAA CEA Individual TSA DANGER IMMUNE RESPONSE TOLERANCE INNATE/AQUIRED IMMUNITY The „multi-hit” model of tumorigenesis Normal epithelial cells 2 APC mutation Inherited Adenomatous polip 1 Ras mutation Adenomatous polip 2 p53 mutation Colon carcinoma Chromosomal translocation Metastatic colon carcinoma Knudson A.G. 2001

  6. VARIOUS ONCOGENES ARE ASSOCIATED WITH DEFINED NEOPLASMS

  7. CHROMOSOMAL TRANSLOCATION IN BURKITT’S LYMPHOMA 8 14 8q- 14q+ CH VH c-myc CH VH c-myc Uncontrolled proliferation due to the activation of c-myc oncogene EBV induced tumor

  8. THE IMMUNE RESPONSE TO TUMORS Hidden, changing, proliferating, evolving target Immune surveillence Few non-self antigens Poorly immunogenic Recognized by B and T lymphocytes Tolerance induction Tumor antigens do exist Recognized primarily by T lymphocytes Induce tolerance TUMOR ANTIGENS Tumor associated antigens – TA Present also in normal cells Aberrant/disregulated expression in tumor cells Tumor specific antigens – TSA Unique for individual tumors or tumor types IMMUNE SYSTEM Tumor-specific immune responses can be induced Cytotoxic T lymphocytes can eradicate tumors

  9. MHC-dependent rejection of tumors

  10. Infective facial tumor in the inbread populations of the Tasmanian devil About 2/3 of Hungary Population half million

  11. Tumor antigens and tumor associated antigens

  12. Tumor-specific antigens

  13. Cancer/testis antigensare expressed almostentirely by cancerous cells, showing little or no expressionin healthy tissue, with the exception of normal testis, embryonic ovaries and placenta. No MHC expression Many of them X-linked Over 100 in total --- Potential targets for immune therapy

  14. STRUCTURE AND SOURCE OF TUMOR ANTIGENS • MUTATED ONCOGENS AND TUMOR SUPPRESSOR GENES • Involved in transformation • Cytosolic novel determinants - no major targets • Cellular proto-oncogenes  oncogeneRas, p53, Abl • Point mutation, deletion, chromosomal translocation, viral gene insertion • ABERRANTLY OVEREXPRESSED NORMAL CELLULAR PROTEINS • Low/rare expression in normal cell – ignorance by the immune system • TUMOR ANTIGENS ENCODED BY GENOMES OF ONCOGENIC VIRUSES • Immunogenic shared viral proteins • DNA viruses – • Simian virus 40, a polyomavirus that is found in both monkeys and humans. (Large T-antigen, binds and inactivates p53) • Herpes, EBV- LMP protein strongly trasforming. Homologue of CD40 • Papilloma HPV16 HPV18 • RNA viruses – • Retroviruses HTLV • ONCOFETAL ANTIGENS • Silenced during development  de-repressed in tumor cells • Tumor markers – carcinoembryonic antigen CEA, specific for carcinomas • Alpha-fetoprotein AFP, hepatocellular carcinoma • TISSUE-SPECIFIC DIFFERENTIATION ANTIGENS • CD10/CALLA Common Acute Lymphoid Leukemia Antigen, Melanoma

  15. NK/γδ macrophage METASTASIS NK/γδ DS CD4/CD8 macrophage Genetic instability Immune selection DS CD4/CD8 TUMOR CD8 ESCAPING TUMOR VARIANTS PROTECTION CD8 Treg cells ELIMINATION Immunsurveillence EQUILIBRIUM ESCAPE

  16. Activation of tumor-specific T-cells by DC Cross-presentation

  17. INDUCTION OF A PROTECTIVE ANTI-TUMOR IMMUNE RESPONSE REQUIRES THE COLLABORATION OF DENDRITIC CELLS AND T-LYMPHOCYTES APOPTOTIC TUMOR CELL IL-2 IFN DC Tumor Ag IL - 12 CROSS PRIMING

  18. CONSEQUENCES OF T-CELL MEDIATED IMMUNITY Cytotoxic T-lymphocytes recognize tumor cells Activated cytotoxic T-lymphocytes kill tumor cells

  19. Manipulation of the immune response by a tumor.

  20. TOLERANCE INDUCTION BY DENDRITIC CELLS Tumor-associated macrophage (upto 40% of non-malignant cells) M1 macrophage: MHCII, CD80, 86 High iNOS, M2 macrphage: arginase + SIGNAL 1 Tumor antigen YES SIGNAL 2 Tumor cell NO Activated APC YES SIGNAL 3 Natural immunity NO Inflammation NO

  21. ESCAPE MECHANISMS OF TUMOR CELLS AND TUMOR TISSUES • TUMOR ANTIGENS • Soluble tumor antigens – inhibit recognition on the cell surface • Antigen modulation – antibody dependent internalization • Masking – antibody binds, no effector function • Low immunogenicity • Peptide antigens – mutations affecting Tc or Th epitopes • ANTIGEN PRESENTATION • Direct presentation – non professional APC, no MHC class II, no co-stimulatory molecules • Indirect presentation – by professional APC, soluble CD40 and CD40 ligand inhibit • CYTOTOXIC T CELL ACTIVITY • MHC – mutation, altered intracellular transport, β2m, locus, allele • Peptide loading – mutation, tumor derived peptides are not presented, TAP • APOPTOSIS • Soluble Fas – inhibits Fas ligand-mediated apoptosis • TUMOR DERIVED INHIBITORY FACTORS • TGFβ – G1 block, inhibits tumor growth if sensitive tumors loose their TGFβ receptor • TGFβ inhibits immune cell activation • PGE2 – immune suppression • TUMOR DERIVED POTENTIATING FACTORS • Angiogenesis factors – secreted by tumor tissue cells or by immune cells

  22. Human epithelial tumours can inhibit the response of lymphocytes expressing NKG2D

  23. Vaccination of melanoma patients may cause their tumor to regress

  24. AZ AKTÍV TUMOR-SPECIFIKUS IMMUNTERÁPIA LEHETŐSÉGEI A tumor antigének beviteli módja ANTI-TUMOR IMMUNOTHERAPY Tumor cell lysate Loaded DC Tumor protein-derived peptide Anti-idiotipe Ab Tumor protein Vírus-tumor genome Plasmid DNA Modified tumor cell Modified DC Irradiated tumor cell Heat shock protein Mocellin S et al. Lancet Oncology 2004

  25. Humanized monoclonal antibodies used in the treatment of patients with cancer.

  26. DIAGNOSIS OF TUMORS BY PET

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