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Ch. 21. Cancer and the Immune System What is cancer? What is the immune response to cancer?

Ch. 21. Cancer and the Immune System What is cancer? What is the immune response to cancer? What are the prospects for immune therapies?. Cancer cells are out of control! Usually derived from a single cell, forming a neoplasm, or tumor Benign tumors are noninvasive;

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Ch. 21. Cancer and the Immune System What is cancer? What is the immune response to cancer?

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  1. Ch. 21. Cancer and the Immune System What is cancer? What is the immune response to cancer? What are the prospects for immune therapies? Ch. 21

  2. Cancer cells are out of control! Usually derived from a single cell, forming a neoplasm, or tumor Benign tumors are noninvasive; malignant tumors can invade and spread (metastasis) Cancers are classified according to their origin Carcinomas vs blood cell cancers: leukemias and lymphomas Ch. 21

  3. Ch. 21 p. 526

  4. How do cells become “transformed” into malignant cells? Radiation Carcinogens Viruses expression of oncogenes (aberrant versions of proto-oncogenes) Ch. 21

  5. Types of regulatory genes Proto-oncogenes- induce proliferation in various ways Tumor suppressors- inhibit cell proliferation Regulators of apoptosis Defects in any of these can lead to uncontrolled cell growth Ch. 21

  6. p. 528 Ch. 21

  7. Mutations accumulate in these cells as they are gradually converted to malignant cells Translocations are associated with certain specific tumors Ch. 21

  8. p. 529 Ch. 21

  9. p. 529 Ch. 21

  10. p. 530 Ch. 21

  11. Immune system tumors Solid or systemic? Acute or chronic? Immature or mature cells? Myelocytic or lymphocytic? Ch. 21

  12. p. 531 Ch. 21

  13. Tumor-specific antigens (TSTA) - found only on tumors chemical or physical carcinogens some viruses: e.g., ATLL, HPV Adult T-Cell Leukemia/Lymphoma Human Papilloma Virus (types 16 & 18) Tumor-associated antigens (TAA) - may be gene products that normally are not expressed (or at the abnormal levels seen in cancer) Can these be isolated and used as vaccines? Diagnosis? Therapy? Ch. 21

  14. p. 532 Ch. 21

  15. p. 534 Ch. 21

  16. Ch. 21

  17. p. 535 Ch. 21

  18. p. 536 Ch. 21

  19. Ch. 21

  20. Ch. 21

  21. Ch. 21

  22. Most tumor antigens are NOT unique to tumors Often these are fetal proteins (e.g., growth factor receptors) CEA- carcinoembryonic antigen AFP- alpha-fetoprotein Oncogene proteins as tumor antigens Neu on human breast cancer cells TATA’s on human melanomas: MAGE1, MAGE-3, BAGE, GAGE-1, GAGE-2. Some shared with other tumors Ch. 21

  23. p. 537 Ch. 21

  24. Immune response to tumors: Ab’s & CMI (after all, it’s altered self) Cell-mediated response of major importance: CTL’s, NK cells (with or w/o ADCC), activated macrophages ~ regression (lytic enzymes, ROI, RNI, TNF-alpha) Many tumors reduce MHC Class I expression NK cells can kill these Also macrophages add NK cells can attack antibody-coated tumor cells (ADCC) Immune surveillance? Ch. 21

  25. Tumors can evade immune response Anti-tumor antibody can block T cell responses (enhance tumor growth) Tumors can modulate antigens – “Ag modulation” (Ab’s bind to Ag on leukemic cells, induce capping, endocytosis of Ag, shedding of Ag-Ab complexes) Tumors can reduce MHC Class I expression (selection; escape CTL recognition) Tumors can reduce “second signal” expression (no B7 -> clonal anergy) im Ch. 21

  26. p. 539 Ch. 21

  27. Strategies for immunotherapy: adjuvant or cytokine Make cells more immunogenic better CTL activation “vaccine” made up of cells? Enhancement of APC activity can modulate tumor immunity BCG – attenuated Mycobacterium bovis mouse dendritic cells incubated with GM-CSF and tumor fragments, then into animal, activate anti-tumor Th and CTL’s Ch. 21

  28. p. 540 Ch. 21

  29. Ch. 21

  30. Cytokine therapy Many have been tried: thanks to recombinant DNA technology interferons (incr. MHC I, MHC II), tumor necrosis factors (TNF), IL-2, -4, -6, -12; GM-CSF Problems: complexity of cytokine interactions hard to administer short half-life serious side effects Ch. 21

  31. LAK cells (lymphokine-activated killer cells) grow blood cells in high levels of IL-2 produce mostly NK cells (NOT tumor-specific) TIL’s (tumor-infiltrating lymphocytes) may have more tumor-specific activity and need less IL-2 Ch. 21

  32. Monoclonal antibodies are useful in treating some tumors Idiotype-specific for B-cell lymphoma: Levy (Stanford) Humanized Anti-HER2 for HER2-receptor-bearing breast cancer Immunotoxins – mAb conjugated to ricin Ch. 21

  33. p. 543 Ch. 21

  34. p. 542 Ch. 21

  35. Cancer vaccines? Antigenic peptides (tumor-specific and immunogenic Delivery (recombinant vaccines) Will they be effectively presented to T cells? Some viral vaccines (e.g., against HPV) may be helpful There is much to be done. Ch. 21

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