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Immunbiology of Tumors

Immunbiology of Tumors. Tumor cells are considered as “parasites” of the body They are formed also in healthy subjects but anti-tumor control mechanism eliminate them Tumor cells escape control with - fast proliferation - mutations - high diversity (“mini evolution”).

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Immunbiology of Tumors

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  1. Immunbiology of Tumors

  2. Tumor cells are considered as “parasites” of the body • They are formed also in healthy subjects but anti-tumor control mechanism eliminate them • Tumor cells escape control with - fast proliferation - mutations - high diversity (“mini evolution”)

  3. Inducers of malignant transformation of cells • chemical carcinogens e.g. tar • physical carcinogens e.g. UV or X-ray • viral - both DNA or RNA viruses

  4. Oncogens • gene coding a protein which can induce malignant transformation - viralorv-onc(they are only exons) • proto-oncogens - are present and function in physiologicallyintact cells - cellular or c-onc(they are exons or introns) • these genes arewell-conservedstructures • their main function is: to modulate proliferationorapoptosis

  5. Neoplastic transformation • genetic alterations • environmental factors • expression of new, non-self cell surface antigens • the non-self antigens are detected by the immune system

  6. Potentialsources of tumor antigens CategoryExample Oncogeneproductmuationin RAS codon 12 (pancr. cc.) bcr/abl protein (chr. myeloidleukemia) Embryonicproteins MAGE family (melanoma, breastcc.) ViralproteinsEpstein-Barrvirus (Hodgkin’slymph.) Hepatitis B (hepaticellularcc.) Tissuespec. antigenTyrosinase (melanoma) Mutant tu. suppressorprot. p53 (severalcc.) IdiotypicepitopesT-cell receptor idiotypes (T-celllymph.)

  7. Formation of Tumor Specific Antigens effect of mutagen mRNA protein MHC changed peptide

  8. Tumor antigens • Tumor specific antigens (TSA) expressed by tumor cells only • Tumor associated antigens (TAA) expressed by tumor cells and some normal cells, too

  9. Characterization of TSA (1) • expression of TSA is induced by chemical carcinogens or X-rays. • somatic mutations result TSA • each carcinogen can induce unique or specific class of TSA

  10. Characterization of TSA (2) • T-cell receptors recognize peptides bound to the antigen - binding to the binding cleft of MHC molecules • TSA that evoke cytotoxic T cell response are derived from peptides uniquely synthesized by tumor cells andexpressed on the surface of MHC I.

  11. CD8+ T cell Normal cell Normal cytoplasmic protein Peptide fragment MHC I antigen CD8+ T cell CD8+ T cell

  12. Responseselicitedby tumor cells Antigen-specific effects on the tumor cell Escapemechanisms Immunologictolerance Apoptosis of tumor cells METASTASIS,DEATH SURVIVAL

  13. Antigen-specific effect of Tc cells MHC I. TCRa Tumor cell Tc TCRb CD8 TNFb FasL Fas APOPTOSIS APOPTOSIS

  14. Mechanisms by which TSAs are derived • Peptides without structural motives for binding to MHC molecules of the host • Mutation in gene encoding converting proteins that convert the peptide to a form binding to MHC and displayed az TSA on cell surface

  15. 40% melanomas expressMAGE-1 (melanomaantigen-encodinggene) 20% breast ca. 30% lung small cell ca. MAGE-1 - embryonal protein, expression is de-repressed in tumors - presentalso in some normal cells e.g. testis

  16. TAA • Oncofetal antigens • Differentialtion specific antigens (DSA)

  17. Oncofetal antigens • normally expressed during a specific phase of enbryogenesis • they are practically in mature, differentiated tuissues • they are not immunogenic • they do not possess functional role in tumor immunity • Their significance: they are diagnostic and prognostic markers • serum cc. correlates with tumormass, level of differentiationand response to therapy

  18. Ideal tumor markers • specific for the typeof the tumor • released onlyin response to tumor • results proportional to tumormass • quantitatively reflects to tumorresponse • elevated even with lowtumor burden

  19. Carcinoembryonic antigen (CEA) • discovered in extracts of adenocc. of colon • a group of heterogeneous glycoproteins - M.W. 200 kD • normally present in embryonic and fetal digestive tissues • detected by RIA or immunoenzymatic technique • elevated (over 5 ng/ml)in gastrointestinal, breast, pancreas, lung tu. and alcoholic cirrhosis, inflammations

  20. Alpha-fetoprotein (AFP) • increased in hepatocellular cc. and malignant teratomas • serum levels are increased in metastatic tumors in liver and acute hepatitis

  21. Prognostic roles of tumor markers † † † 1000 Se AFP ng/ml 100 chemotherapy - no response chemotherapy - response surgery with regrowth or metastasis surgery

  22. In experimental model TSA assessed by: • ability to resist a live tumor implant following the immunization with tumor cells • ability to resist when the model is infused with sensitized T cells from a syngeneic donor • in vitro demonstration of tumor cell destruction by cytotoxic T cells gained from a tumor immunized animal

  23. Host immune response to tumorExperimental • Colony inhibition of tumorsby sensitized lymphocytes • Tumor extracts induce lymphocyte blast tratnsformation • Lymphocyte-enhanced cytotoxicity • Macrophage-enhanced phagocytosis

  24. Host immune response to tumorsClinical • Spontaneous regression • Regression of tu. - sublethal doses of chemotherapy • Regression of metastasis - resection of primary tumor • Mononuclear cell infiltration • High incidence of tu. after clinical immunospureassion • High incidence of tu in immunodeficiency • Increased incidence of tu. in aging

  25. Cellular effectors that mediate immunity (1) • Cytotoxic T-Ly - protective role against virus- associated neoplasms (e.g. EBV) • NK-Ly - capable to destroy tumor cells w\o prior sensitization • Only tu. cells w\o MHC are lysed: NK-Ly recognize carbohydrate components of the membrane by NKR-P1 rec. BUT Ly49 rec. recognize MHC I. and blocks NK-Ly activity (This is the first-line of defense.) • Activation with IL-2: NK Ly lyse a variety of tu. T Ly Complementary anti-tumor mechanisms NK Ly

  26. Cellular effectors that mediate immunity (2) • Macrophages (activated) possess selective cytotoxicity against tumor cells T Ly NK Ly collaborate in anti-tumor reactivity Macrophages (e.g. INF-g secreted by T and NK Ly activator of macrophages. Production of reactive oxygen, or secretioon of TNF-a) • Humoral mechanisms: activation of complement induction of ADCC by NK Ly

  27. Cellular effectors of antitumor immunity IL-2 CTL NK Ly Peptide TC-rec. NK-rec. MHC I Antigen IgG INF-g TNF-a Fc-rec. Macrophage NK Ly

  28. Effector Mechanisms in Tumor Immunity Humoral: • opsonisationand phagocytosis • complementmediated lysis • loss of cell adhesion(antibody dependent) Cellular: • T Ly • Antibody-dependent cytotoxicity • NK Ly • Lymphokine-activated killer (LAK) cells • Macrophages (also activated by lymphokines)

  29. Immuno Surveillance • In5% with congenital immunodeficiencies develop cancer (200x rate) • Inimmunsuppressed patients (80x rate) • AIDS, lymphomas, chronic infectious mononucleosis or malignant lymphomas

  30. Escape of Tumors • Continuousshedding of tumor antigens - solubile antigens Reults: - impossible to detect selectively these cells - only NK-Ly can detect these cells, BUTthey are not present everywhere

  31. KAR KIR + Effects of NK on the target cells Killer inhibitory receptor = KIR; Killer activator receptor = KAR target MHC I KAR KIR + - NK-Ly NO apoptosis Apoptosis

  32. More Escape Mechanisms from Immuno Surveillance • selective outgrowth of antigen negative variants • loss or reduced expression of HLA antigens • no costimulation- no sensitization- anergic T Ly - apoptosis of T Ly • expression of local inhibitorymolecules(TNF- borFas ligand • immunosuppression (chemicals, radiation, TGF-b)

  33. Immunologicactivation and tolerance Viralinfection Cancer V Dangersignals (GM-CSF, TNF-a) Antigen uptake by activated APC T cell V V Costimulatory signal (B7, Il-12) T cell T cell Tumor-specific T cellsbecome tolerant Virus-specific T cellsbecome activated

  34. Failure of Immune Response to Tumor • Some tumors arise in areas not accessible to the effector cells (e.g. eye, CNS) • Antigenic modulation - antigensof tumor cells may undergo several changes • Blocking factors - immune complexes or cytophilic antibodies can mask tumor antigens or prevent binding by effector cells or lytic antibodies

  35. Prospects for Immunotherapy to generate antitumor responses (1)1890 WiliamColey: bacterialextractstoactivategeneralimmunity • Tumor cell vaccines - there areT cells directed against the tumor - their number could be increased with autologous or allogeneictumor cells (the replication is prevented by irradiation) • Immunization with tumor-specific peptides - only for tumors for whichTAAhave been cloned and peptides synthesised • Cytokine therapy - increasingthe levels of some cytokines (IL-2, IFN, GM-CSF, IL-7, IL-12) Problems:short life-time, toxicity, non-specific cytokines.

  36. Prospects for Immunotherapy to generate antitumor responses (2) • Monoclonal antibodies - used to deliverimmunotoxins. radioisotopes, drugs. Bivalent antibodies recognize both T cells and TAA - they guide T cell to the tumor. • Gene therapy - combines the concepts of “tumor cell vaccines” and “cytokine therapy” by expressing genes coding for cytokines, costimulatory molecules or MHC. • Adoptive immunotherapy - with antitumor cells, tumor infiltrating lymphocytes (TIL) or lymphokine-activated killer (LAK) cells. Problems: growing the large number of cells required, loss of antigene specificity for T cells, altered homing pattern

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