TUMOR IMMUNOLOGY • Tumor antigens • Effector mechanisms in anti-tumor immunity • Mechanisms of tumor evasion of the immune system • Immunotherapy for tumors 1 Harvard-MIT Division of Health Sciences and TechnologyHST.176: Cellular and Molecular ImmunologyCourse Director: Dr. Shiv PillaiImmunosurveillance • An hypothesis that states that a physiologic function of the immune system is to recognize and destroy malignantly transformed cells before they grow into tumors. • Proposed by Paul Ehrlich, Macfarlane Burnet and Lewis Thomas • Implies that cells of the immune system recognize something “foreign” on transformed/tumor cells. Evidence in Support of Immunosurveillance (I) • Immunodeficient individuals are more likely to develop certain types of tumors than immunocompetent individuals. • Clinicopathologic correlations suggest that lymphocytic infiltrates in some tumors (e.g. medullary breast carcinoma, malignant melanoma) are associated with a better prognosis compared to histologically similar tumors without infiltrates 2Evidence in Support of Immunosurveillance (I) • Immunodeficient individuals are more likely to develop certain types of tumors than immunocompetent individuals. • Clinicopathologic correlations suggest that lymphocytic infiltrates in some tumors (e.g. medullary breast carcinoma, malignant melanoma) are associated with a better prognosis compared to histologically similar tumors without infiltrates 3Evidence in Support of Immunosurveillance (II) • Histologic evidence indicates that active immune responses occur within tumors or in draining lymph nodes. • There is ample evidence that T and B lymphocytes specific for tumor surface molecules have been activated and expanded in tumor patients. 4Evidence in Support of Immunosurveillance (II) • Histologic evidence indicates that active immune responses occur within tumors or in draining lymph nodes. • There is ample evidence that T and B lymphocytes specific for tumor surface molecules have been activated and expanded in tumor patients. 5Tumor Immunosurveillance; Qualified • Since common cancers (e.g. carcinomas of lung, colon, breast, prostate) arise frequently in immunocompetent individuals, immunosurveillance is often not effective. • Since many of the tumors which arise frequently in immunodeficient individuals are likely caused by oncogenic viruses (e.g. EBV, HPV), effective tumor immunosurveillance may reflect effective anti-viral immunity. 6Tumor Immunosurveillance; Qualified See Immunobiology, by Janeway,C., Travers, P.,Walport, M. and Capra, J., Garland Publishing, 5th edition, 2001 & Cellular and Molecular Immunology by Abbas, A., Pober, J., and Lichtman, A., W B Saunders; 4th edition.Transplantation Antigens on Chemically Induced Tumors Immunization with killed tumor cells from: Challenge with live tumor cells from: Result Conclusion Chemically induced sarcoma A Chemically induced sarcoma A No growth Chemically induced sarcoma A Chemically induced sarcoma B Growth of tumor B Immunity is specific for individual tumor Transplantation Antigens on Virally Induced Tumors Immunization with killed tumor cells from: Challenge with live tumor cells from: Result Conclusion MSV -induced sarcoma A MSV-induced sarcoma A No growth MSV-induced sarcoma A MSV-induced sarcoma B No growth MSV-induced sarcoma A Chemically -induced sarcoma C Growth MSV -induced sarcoma A MuLV-induced sarcoma D Growth Immunnity to virus induced tumors is virus-specific 8Patterns of Tumor Antigen Expression • Tumor specific antigens (TSAs): Expressed on tumor cells but not normal cells. – Unique tumor antigens on one tumor only – Antigens shared between tumors of same type – Tumor-specific transplantation antigens (TSTAs) • Tumor associated antigens (TAAs): Expressed on normal cells and tumor cells. – Differentiation antigens TUMOR ANTIGENS • Tumor Antigens Recognized by Host T Lymphocytes • Tumor Antigens Recognized by Antibodies – Antibodies produced by host humoral responses – Antibodies raised in animals used as diagnostic, therapeutic agents 910 IMMUNITY TO TRANSPLANTED TUMORS CAN BE TRANSFERRED BY CTLSFigure removed due to copyright restrictions.27 IDENTIFICATION OF TUMOR ANTIGENS RECOGNIZED BY T LYMPHOCYTES • Transplantation studies of tumors in rodents. • The establishment of cloned CTL lines which recognize • The identification of the peptide-antigens which induce CTL responses in tumor patients, and the the genes encoding the proteins from which the peptides are derived. tumor antigens (humans).IDENTIFICATION OF TUMOR ANTIGENS RECOGNIZED BY T LYMPHOCYTES See Immunobiology, by Janeway,C., Travers, P.,Walport, M. and Capra, J., Garland Publishing, 5th edition, 2001 & Cellular and Molecular Immunology by Abbas, A., Pober, J., and Lichtman, A., W B Saunders; 4th edition.Examples of Tumor Antigens that Stimulate T Cell Responses (I) See Immunobiology, by Janeway,C., Travers, P.,Walport, M. and Capra, J., Garland Publishing, 5th edition, 2001 & Cellular and Molecular Immunology by Abbas, A., Pober, J., and Lichtman, A., W B Saunders; 4th edition.Examples of Tumor Antigens that Stimulate T Cell Responses (II) • Viral gene products in virus- associated malignancies. – SV40 T antigen (SV40-induced rat tumors) – Human papillomavirus E6 and E7 gene products (human cervical carcinoma) – Epstein-Barr virus EBNA-1 gene product (Burkitt's, lymphoma and nasopharyngeal carcinoma) 14Melanoma Antigens • Properties of melanomas that facilitate the study of tumor antigens. – Readily excisable from skin – Can be grown in tissue culture – Often elicit a marked lymphocytic response • Studies of melanoma antigens – Establishment of cloned CTL lines specific for melanomas – Identification of melanoma proteins recognized by CTL Melanoma Tumor Antigens Recognized by CTLs • Tumor-associated testis-specific antigens-normally not expressed (“silent” ) in most tissues – MAGE, BAGE, GAGE (expressed by many human melanomas, many types of carcinomas, normal testis) • Tissue specific antigens: – Tyrosinase, Mart-1, gp100 (expressed by normal melanocytes): • Mutated or aberrantly expressed molecules – MUM-1 (point mutation of gene of unknown function) – beta-catenin 15Tumor Antigens Recognized by T Lymphocytes: Review • Products of mutated normal cellular genes not related to oncogenesis • Products of oncogenes and mutated tumor