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2. Objectives
3. Definitions of Cancer and Carcinogenesis
4.
5. Classification of cancer
6. Carcinogens
7. Tumor Immunology
8. Tumors stimulate an immune response
9. Oncogenesis proto-oncogenes tumor suppressor genes oncogenes carcinogen results in mutation dysfunctionaltumor suppressor genes inherited defect increased GF increased GF receptors exaggerated response to GF loss of ability to repair damagedcells or induce apoptosis 10. Tumor Associated Antigens
11. Four mechanisms of oncogene activity to deregulate cell division 12. A closer look at p53 13. Cancer cells are different
14. EXPERIMENTAL EVIDENCE FOR TUMOR ANTIGENS AND IMMUNE RESPONSE 15. TUMOR OVEREXPRESSION OF NORMAL AG 16. Immunity against tumor All components, specific and nonspecific, humoral and cellular affect tumor progression and growth 17. Tumor Surveillance
18. Tumors can both activate and suppress immunity Tumors can activate the immune response (ex. expression of foreign antigen with MHCI) or suppress the immune response (activation of T regulatory cells that release IL-10 and TGF ) the balance determines whether the cancer becomes clinically relevant or not Khong,H. T.et al. Nature Immunology3, 999 - 1005 (2002) 19. Basic Tumor Immunosurveillance
20. MACMHC II MAC T helper cell IL-2 T helper Memory cell T helper effectorcell IL-1 Interferon Macrophages and dendritic cells can directly attack tumor cells, or more commonly can express exogenous antigens (TSAs or bits of killed tumor cells) to CD4 cells Tumor cell or tumor derived antigen Dendritic and Macrophage Presentation of Tumor Antigen to CD4 Cells 21. MAC or B cell (APC) MHC 1 T cytotoxic cell Perforins, apoptotic signals Exogenous antigen T cytotoxic memory cells T cytotoxic effector cells T Cytotoxic Cell Activity in Tumor Surveillance Cancer Cell T cytotoxic cell Endogenous antigen 22. MACMHC II MHC I APC T helper cell T helper 2 cell IL-2 B CellEosinophilIL-4 IL-5 T helper Memory cell T helper Effectorcell IL-1 T cytotoxic cell T cytotoxic memory cells T cytotoxic effector cells Perforins, apoptotic signals Interferon 1 Cancer Cell T cytotoxic cell Endogenous antigen Perforins, apoptotic signals Generally ineffective tumor surveillance, but some ADCC Tumor antigen or tumor cell SUMMARY 23. TARGET CELL Y Y MAC OR NK Antibody-dependent cell-mediated cytotoxicity (ADCC)Y 24. NATURAL KILLER CELL Do not recognize tumor cell via antigen specific cell surface receptor, but rather through receptors that recognize loss of expression of MHC I molecules, therefore detect missing self common in cancer. NKTarget cell (infected or cancerous) Perforin and enzymes killer activating receptor 25. Tumor surveillance by NK Cells Tumor cells produce reactive oxygen species and stress induced ligands that can be recognized by NK cells 26. Tumor Escape Mechanisms
27. Lack of MHCI as a tumor escape mechanism Defects in mechanisms of MHCI production can render cancer cells invisible to CD8 cells 28. Tumors can escape immunity (and immunotherapy) by selecting for resistant clones that have occurred due to genetic instability 29. Immunoediting of cancer cells Eliminationrefers to effective immune surveillance for clones that express TSA Equilibriumrefers to the selection for resistant clones (red) Escaperefers to the rapid proliferation of resistant clones in the immunocompetent host 30. 1) Tumor cell production of immune suppressants such as TGF- ,2) T regulatory cell stimulation with production ofimmune suppressants such as TGF- 1 2 Avoidance of tumor surveillance through release of immune suppressants MaparaJournal of Clinical Oncology. 22(6):1136-51, 2004 31. Tumor cells induce apoptosis in T lymphocytes via FAS activation
32. Issues in Immunocompetence and Cancer
33. Approaches to Cancer Immunotherapy
34. Cytokines
35. Tumor Vaccines
36.
Turning on the immune response to tumor cells through administration of immune stimulants 37. DNA vaccination with antigen expressed on MHC 38. DNA vaccine (viral vector) to induce costimulatory factors and cytokines 39. Dendritic cell vaccinedendritic cells undergo viral transduction of more effectively present antigen 40. SEROTHERAPY: Monoclonal Antibodies To Tumor Antigens 41. Additional mechanisms of antitumor activity with monoclonal antibodies
42. TUMOR ESCAPE MECHANISMS T regulatory cells Or kill them Or T regulatory cells