Tumor immunology mahlet

• 1. Tumor immunology Integrating Immunitys Roles in Cancer Suppression and Promotion 1

2. Objectives Answer the question, how the immune system affects cancer development & progression? 2 3. Modern concepts in carcinogenesis 4. Modern concepts in carcinogenesis viral etiology mutated onco-proteins over-expression normal antigens generation of antigen specific immune responses sophisticated mechanisms triggering of multiple pathways impairment of T cell anti-tumor responses 5. Variable intermediaries Tregs pDC suppressor macrophages MDSC regulate T cell responses bioavailability of L-arg 6. Alterations of Immune Response in cancer dysfunctional immune response loss of DTH blocking antibodies suppressor factors suppressor macrophages development of characteristic opportunistic infections? T cell responses against bacterial and/or chemical antigens 7. ability of Tumors to suppress T responses? failure of immunotherapy loss of T cell responses vaccine trials demonstrated progression of tumors robust T cell response cellular and molecular models T cell anergy 8. discovery of several mechanisms role of immunoregulatory molecules in APC B7.1, B7.2, B7-H1 & B7-H4 development of Tregs tumor-induced accumulation of MDSCs initiators of suppression tumor cells APCs(DCs & Ms) MDSC 9. Tumor cells? tumor cells produce VEGF G-CSF GM-CSF arrested differentiation of myeloid cells block T cell responses IL-10, TGF- & PGE2 accumulation of immature myeloid cells head & neck, breast, and lung cancer 10. mechanisms by which T cells become suppressed multiple, but discrete changes in expression of CD3 (H2O2) tyrosine kinases p56lck, p59fyn upregulate Jak-3 translocate NFkBp65 diminished ability to mobilize Ca++ decreased tyrosine phosphorylation renal cell carcinoma, melanoma, Hodgkins disease, ovarian cancer, colon carcinoma, & cervical cancer 11. CD3 oxygen scavengers radicals (H2O2) increased number of activated neutrophils pancreatic & breast cancer chronic stimulation of T cells by specific antigens 12. Metabolism of L-Arg by Myeloid Cells L-Arg substrate for NOS1, NOS2, & NOS3 Arginase I and II Arginine: glycine amidinotransferase (AGLT) L-Arg decarboxylase (ADC) dietary L-Arg is taken up by intestinal epithelial cells transported via y+ system of cationic amino acid transporters (CAT) 13. Raber et al., 2012 14. expression of arginase I and NOS2 in murine macrophages differentially regulated Th1 & Th2 cytokines IFN- up-regulates NOS2 exclusively IL-4, IL-10 and IL-13 induce arginase I arginase II mitochondrial isoform modulation by Th1 or Th2 cytokines? 15. Tumor immunology Integrating Immunitys Roles in Cancer Suppression and Promotion 15 16. Immunitys Roles in Cancer Suppression & Promotion immune system plays a dual role in cancer: suppress tumor growth by destroying cancer cells or inhibiting their outgrowth promote tumor progression by selecting for tumor cells that are more fit to survive in an immunocompetent host by establishing conditions within tumor microenvironment that facilitate tumor outgrowth 16 17. Tumor immunology Can immune system control cancer? subject of debate for over a century Paul Ehrlich (1900) that cancer would be quite common in long- lived organisms if not for the protective effects of immunity How?? 50 yrs 17 18. cancer immunosurveillance hypothesis Burnet and Thomas adaptive immunity was responsible for preventing cancer development in immunocompetent hosts Stutman challenged this hypothesis similar susceptibility of immunocompetent & nude mice largely abandoned why cancer immunosurveillance could not possibly occur? 18 19. cancer immunosurveillance hypothesis danger signals in tumor cells? ignorance or tolerance to a developing tumor persistent activation of innate, pro- inflammatory arm of immunity facilitate cellular transformation & promote cancer outgrowth 19 20. cancer immunosurveillance hypothesis improved mouse models of immunodeficiency on pure genetic backgrounds reassess role of immunity in cancer control rekindled immunosurveillance hypothesis: IFN inducing rejection of transplanted tumor cells mice lacking either IFN responsiveness lacking either IFN R or STAT1 transcription or adaptive immunity [RAG2/] more susceptible to carcinogen induced & spontaneous primary tumor formation the immune system can function as an extrinsic tumor suppressor 20 21. Immunitys Roles in Cancer 3 distinct roles in preventing cancer: protects host against viral infection suppresses virus-induced tumors it prevents establishment of an inflammatory environment tumorigenesis by eliminating pathogens & prompt resolution of inflammation it eliminates tumor cells in certain tissues 21 22. Tumor Antigens & Cancer Immunosurveillance fundamental tenet of tumor immunology in general & of cancer immunosurveillance cancer cells express antigens differentiate them from their non-transformed counterparts mice immunized with chemically induced tumors protected against subsequent re-challenge with same tumor transplantation rejection antigens 22 23. Tumor Antigens molecular studies revealed that these antigens were products of mutated cellular genes aberrantly expressed normal genes genes encoding viral proteins 23 24. Tumor Antigens human tumor antigens include: differentiation antigens (melanocyte differentiation) mutational antigens (such as p53) over expressed cellular antigens (such as HER-2) viral antigens (such as HPV proteins) cancer/testis (CT) antigens 24 25. The Cancer Immunoediting Hypothesis The discovery in 2001 the immune system controls not only tumor quantity but also tumor quality (immunogenicity) prompted a major revision of cancer immunosurveillance hypothesis 25 26. 26 27. The Cancer Immunoediting Hypothesis the immune system not only protects host against tumor formation but also shapes tumor immunogenicity is basis of cancer immunoediting hypothesis stresses dual host-protective & tumor- promoting actions of immunity on developing tumors 27 28. The Cancer Immunoediting Hypothesis cancer immunoediting process in its most complex embodiment, proceeds sequentially through 3 distinct phases: elimination equilibrium escape 28 29. The Cancer Immunoediting Hypothesis in some cases tumor cells may directly enter into either equilibrium or escape phases external factors may influence directionality of flow: environmental stress immune system deterioration accompanying aging immunotherapeutic intervention on tumor cell outgrowth in human cancer patients 29 30. 30 31. Elimination pahse transformed cells develop after failure of intrinsic tumor suppressor mechanism initiate stromal remodeling which results in local tissue disruption recognized as a danger signal by cells of innate immune system NK cells, NKT, T cells & macrophages interaction of these cells triggers extrinsic tumor suppressive mechanism: generation of IFN- and ILs by NK cells and macrophages 31 32. Elimination phase INF- activates antiproliferative, proapoptotic & angiostatic processes lead to death of a significant number of tumor cells Macrophages by production of ROS & RNI NK cell via TRAIL or perforin dependent mechanisms together kill the residual tumor cells 32 33. Elimination phase killing generates tumor antigens which activate DCs recruited at the tumor site DC capture tumor antigens & migrate to LNs activate nave Th1 CD4+ T cells CD8+ cytotoxic lymphocytes (CTL) tumor specific CD4+ and CD8+ T cells migrate to tumor site to kill viable antigen positive tumor cells 33 34. Elimination phase CD4+ T cells produce IL-2 keeps tumor specific CD8+ T cells activated CD8+ T cells recognize kill the tumor cells directly by IFN- dependent mechanisms of cell cycle inhibition, apoptosis, and angiostasis by induction of macrophage tumoricidal 34 35. 35 36. Does the Equilibrium Phase Really Exist? explain the period of immune dormancy experienced phenomenon of relapse seen in many cancers after one to two decades of remission immune system controlling, but not eliminating 36 37. Evidences to equilibrium phase of cancer occurrence of minimal residual disease (MRD) in leukemia and some solid malignancies lends further support to equilibrium hypothesis MRD small number of malignant cells remain in body below threshold of conventional morphologic or cytogenetic recognition 37 38. Evidences to equilibrium phase of cancer preneoplastic conditions like monoclonal gammopathy of undetermined significance (MGUS) existence of an immune response to premalignant MGUS cells that eventually progress to multiple myeloma (MM) 38 39. What are the Mechanisms Involved in Equilibrium? solely maintained by adaptive immunity in contrast to the other two phases significant reduction in tumor progression in case of infiltration of tumor by the T lymphocytes extent of involvement of CD4+CD25+Foxp3+ T cells or Treg??? role of cytokines like IFN- and TNF has also been suggested by some studies 39 40. Evidences to equilibrium phase of cancer immunogenicity of cancer cells also varies during the three stages more immunogenic in equilibrium phase Where do they hide? reside in niches made up of specialized vascular bed of endothelial cells, associated stromal cells of mesenchymal origin & extracellular matrix components 40 41. 41 42. How does Tumor Evade Equilibrium? by complex interplay of cancer cells, the cytokines and the immune cells the tumor sheds all its antigens & other molecules which immune cells use for their recognition i.e. MHC, NKG2D tumor cells which in turn induce CTLA-4 immuno suppresive state is accentuate by secretion of cytokines like TGF- and IL-10 42 43. 43