1. Tumour immunology Prof M.I.N. Matee

9. Oncogenesis proto-oncogenes tumor suppressor genes oncogenes carcinogen results in mutation dysfunctional tumor suppressor genes inherited defect increased GF increased GF receptors exaggerated response to GF loss of ability to repair damaged cells or induce apoptosis

11. Four mechanisms of oncogene activity to deregulate cell division

12. A closer look at p53

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

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 Immunology 3, 999 - 1005 (2002)

20. MAC MHC 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 (TSA’s 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. MAC MHC II MHC I APC T helper cell T helper 2 cell IL-2 B Cell Eosinophil IL-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. NK Target 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

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 Elimination refers to effective immune surveillance for clones that express TSA Equilibrium refers to the selection for resistant clones (red) Escape refers 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 of immune suppressants such as TGF-  1 2 Avoidance of tumor surveillance through release of immune suppressants Mapara Journal of Clinical Oncology. 22(6):1136-51, 2004

37. DNA vaccination with antigen expressed on MHC

38. DNA vaccine (viral vector) to induce costimulatory factors and cytokines

39. Dendritic cell vaccine – dendritic cells undergo viral transduction of more effectively present antigen

40. SEROTHERAPY: Monoclonal Antibodies To Tumor Antigens

42. TUMOR ESCAPE MECHANISMS T regulatory cells Or kill them Or T regulatory cells