Tumor Immunology (I): Cancer Immunosurveillance & Immunoediting Masoud H. Manjili Department of Microbiology & Immunology Goodwin Research Building-286 (804)

Learning Objectives n n Immune surveillance and immune editing of cancer n n Immunotherapy of cancer

Goal of Tumor Immunology The ultimate goal of tumor immunology is to induce clinically effective anti-tumor immune responses that would discriminate between tumor cells and normal cells in cancer patients

Cancer is the second leading causes of death in the US

Types of Cancer n n Carcinoma: arising from epithelial tissue, such as glands, breast, skin, and linings of the urogenital, digestive, and respiratory systems (89.3% of all cancers) n n Lymphoma, Myeloma: diseases of the lymph nodes and spleen that cause excessive production of lymphocytes (5.4% of cancers) n n Leukemia: disease of bone marrow causing excessive production of leukocytes (3.4% of all cancers) n n Sarcoma: solid tumors of muscles, bone, and cartilage that arise from the embryological mesoderm (1.9% of all cancers)

Etiology of Cancer Transformation of germline cells: inheritable cancers (<10%, Rb, BRCA1, 2) Transformation of somatic cells: noninheritable cancers (>90%) Environmental factors: UV (skin cancer), chemicals (lung cancer), pathogens (HPV causes cervical cancer, helicobacter causes stomach cancer)

Genetic Factors

Environmental Factors

Discovery of anti-tumor immune response

Evidence for Tumor Immunity n n Spontaneous regression: melanoma, lymphoma n n Regression of metastases after removal of primary tumor: pulmonary metastases from renal carcinoma n n Infiltration of tumors by lymphocytes and macrophages: melanoma and breast cancer n n Lymphocyte proliferation in draining lymph nodes n n Higher incidence of cancer after immunosuppression, immunodeficiency (AIDS, neonates), aging, etc.

Anti-tumor immunity via cross priming

Tumor Immunology n n Cancer immunosurveilance: immune system can recognize and destroy nascent transformed cells n n Cancer immunoediting: tumors tend to be genetically unstable; thus immune system can kill and also induce changes in the tumor resulting in tumor escape and recurrence

Evidence for Elimination (cancer immunosurveillance) n n Mice lacking perforin show an increased frequency of lymphomas n n Mice lacking RAG and STAT1 develop gut epithelial and breast tumors n n Mice lacking gamma delta T cells are susceptible to skin tumors induced by topical application of carciongens n n Immunosurveillance is against virus- associated tumors rather than against common spontaneous tumors

Elimination or Tolerance? affinity

Elimination: mutated tumor antigens

Elimination: abnormal expression of antigens

Evidence for Equilibrium (occult tumors) The occurrence of cancer in recipients of organ transplants: melanoma after kidney transplant

Evidence for Escape (detectable tumors) 1) 1) Immune responses change tumors such that tumors will no longer be seen by the immune system: tumor escape 2) 2) Tumors change the immune responses by promoting immune suppressor cells: immune evasion

Escape: immune system sculpts tumors GM-CSF VEGF MCP-1 MDSC

Summary n n Environmental factors such as UV, chemicals, pathogens (viral and bacterial infections) n n Immune responses have a dual function: immunosurveillance and immunoediting of tumor (elimination, equilibrium, escape) n n Immunoediting: immune responses can change tumors to be hidden from recognition by the immune system and tumors can promote immune suppressor cells: T regs and myeloid-derived suppressor cells (MDSC)

Suggested Reading Janeway’s Immunobiology, 7 th edition: Chapter 15; Pgs