Tumor Immunology (I): Cancer Immunosurveillance
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Tumor Immunology (I): Cancer Immunosurveillance

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  • Discovery of tumor antigens: Induction of cancer in animals by chemical carcinogens such as Meth A or irradiation; 2) development of inbred animals in which these tumors can be seen as self (MHC match)
  • RAG: recombination activating gene encode enzymes that play an important role in the rearrangement and recombination of the genes of immunoglobulin and T cell receptor molecules during the process of VDJ recombination . RAG1 and 2 are restricted to lymphocytes Millions of Abs T cells are created by shuffling a few hundred genes in a process of VDJ recombination. RAG-1 and RAG-2 are proteins at the ends of VDJ genes that separate, shuffle, and rejoin the VDJ genes. This shuffling takes place inside B cells and T cells during their maturation.
  • Privileged site: grow in nodules surrounded by physical barriers such as collagen and fibrin.

Tumor Immunology (I): Cancer Immunosurveillance Tumor Immunology (I): Cancer Immunosurveillance Presentation Transcript

  • Tumor Immunology (I): Cancer Immunosurveillance & Immunoediting Masoud H. Manjili Department of Microbiology & Immunology Goodwin Research Building-286 (804) 828-8779
  • Learning Objectives
    • Immune surveillance and immune editing of cancer
    • 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
    • Carcinoma: arising from epithelial tissue, such as glands, breast, skin, and linings of the urogenital, digestive, and respiratory systems (89.3% of all cancers)
    • Lymphoma, Myeloma: diseases of the lymph nodes and spleen that cause excessive production of lymphocytes (5.4% of cancers)
    • Leukemia: disease of bone marrow causing excessive production of leukocytes (3.4% of all cancers)
    • 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
    • Spontaneous regression: melanoma, lymphoma
    • Regression of metastases after removal of primary tumor: pulmonary metastases from renal carcinoma
    • Infiltration of tumors by lymphocytes and macrophages: melanoma and breast cancer
    • Lymphocyte proliferation in draining lymph nodes
    • Higher incidence of cancer after immunosuppression, immunodeficiency (AIDS, neonates), aging, etc.
  • Anti-tumor immunity via cross priming
  • Tumor Immunology
    • Cancer immunosurveilance:
    • immune system can recognize and destroy nascent transformed cells
    • 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)
    • Mice lacking perforin show an increased frequency of lymphomas
    • Mice lacking RAG and STAT1 develop gut epithelial and breast tumors
    • Mice lacking gamma delta T cells are susceptible to skin tumors induced by topical application of carciongens
    • 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)
    • Immune responses change tumors such that tumors will no longer be seen by the immune system: tumor escape
    • Tumors change the immune responses by promoting immune suppressor cells: immune evasion
  • Escape: immune system sculpts tumors GM-CSF VEGF MCP-1 MDSC
  • Summary
    • Environmental factors such as UV, chemicals, pathogens (viral and bacterial infections)
    • Immune responses have a dual function: immunosurveillance and immunoediting of tumor (elimination, equilibrium, escape)
    • 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. 672-678