1. Tumor Immunology (I): Cancer Immunosurveillance & Immunoediting Masoud H. Manjili Department of Microbiology & Immunology Goodwin Research Building-286 (804) 828-8779

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

3. 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

4. Cancer is the second leading causes of death in the US

5. 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)

6. Etiology of Cancer 1. 1. Transformation of germline cells: inheritable cancers (<10%, Rb, BRCA1, 2) 2. 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)

7. Genetic Factors

8. Environmental Factors

9. Discovery of anti-tumor immune response

10. 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.

11. Anti-tumor immunity via cross priming

12. 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

14. 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

15. Elimination or Tolerance? affinity

16. Elimination: mutated tumor antigens

17. Elimination: abnormal expression of antigens

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

19. 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

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

21. 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)

22. Suggested Reading Janeway’s Immunobiology, 7 th edition: Chapter 15; Pgs. 672-678