Cancer Immunology


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Cancer Immunology

  1. 1. Mitzi Nagarkatti, PhD Professor and Chair Dept. of Pathology, Microbiology and Immunology School of Medicine and Deputy Director, Basic and Translational Research South Carolina Cancer Center University of South Carolina Tel. # (803)733-3275 E-mail: Tumor Immunology
  2. 2. Objectives <ul><li>Introduction </li></ul><ul><li>Ags expressed by cancer cells </li></ul><ul><li>Nature of immune response </li></ul><ul><li>How cancer evades immune system </li></ul><ul><li>Immunotherapy </li></ul>
  3. 3. Cancer Introduction <ul><li>Uncontrolled growth produces a tumor or neoplasm. </li></ul><ul><li>A tumor that grows indefinitely and often spreads (metastasis) is called malignant --also called cancer. </li></ul><ul><li>A tumor that is not capable of indefinite growth---- benign. </li></ul><ul><li>Malignant---kills host. </li></ul><ul><li>Benign---does not kill host. </li></ul>
  4. 4. Cell Growth Control of cell growth Growth-promoting Proto-oncogenes Growth-restricting Tumor-suppressor genes
  5. 5. Molecular Basis of Cancer Uncontrolled cell growth Proto-oncogenes Tumor-suppressor genes Mutations Radiation Chemical (Carcinogen) Virus
  6. 6. Types of cancers based on etiologic agent <ul><li>Chemically-induced tumors </li></ul><ul><ul><li>Each tumor induced by a carcinogen (e.g. benzopyrene) injected at various sites expresses a unique Ag. </li></ul></ul><ul><ul><li>Thus difficult to develop vaccine. </li></ul></ul><ul><li>Virus-induced tumors </li></ul><ul><ul><li>Tumors induced by same virus express same tumor Ag. </li></ul></ul><ul><ul><li>Induce a strong immune response. </li></ul></ul><ul><ul><li>e.g. Gardasil vaccine – Human Papilloma Virus (HPV) induced cervical cancer </li></ul></ul><ul><li>UV-induced tumors </li></ul><ul><ul><li>UV radiation--->melanomas </li></ul></ul><ul><ul><li>Highly tumorigenic </li></ul></ul>
  7. 7. Virus-induced tumors e.g.SV40
  8. 8. Chemical-induced tumors e.g. methylcholanthrene
  9. 9. Types of Cancer based on the tissue affected <ul><li>Carcinoma : Cancer of endo or ectoderm e.g. Skin or epithelial lining of organs </li></ul><ul><li>Sarcomas : Cancer of mesoderm e.g. bone </li></ul><ul><li>Leukemias and Lymphomas : Cancers of hematopoietic cells </li></ul>
  10. 10. Evidence for the role of immune system in tumor rejection <ul><li>Spontaneous regression </li></ul><ul><li>Infiltration of tumors by lymphocytes and macrophages </li></ul><ul><li>Regression of metastases after removal of primary tumor </li></ul><ul><li>Regression after chemotherapy </li></ul><ul><li>Lymphocyte proliferation in draining lymph nodes </li></ul><ul><li>Higher incidence of cancer after immunosuppression/immunodeficiency (AIDS, neonates, aged, transplant patients) </li></ul>
  11. 11. Antigens expressed on tumor cells Major Histocompatability Complex antigens TSTA TATA TSTA : unique to a tumor Play an important role in tumor rejection. TATA : shared by normal and tumor cells Tumor-associated developmental Ag (TADA) Tumor-associated viral Ag (TAVA) Tumor-specific transplantation Ag Tumor-associated transplantation Ag
  12. 12. Tumor-Associated Developmental Ags <ul><li>Found on cancer cells and on fetal cells. </li></ul><ul><li>Do not trigger anti-tumor immunity. </li></ul><ul><li>Used in diagnosis. </li></ul><ul><ul><li>Alpha-fetoprotein(AFP) Cancers of liver </li></ul></ul><ul><ul><li>Carcinoembryonic Ag (CEA) colorectal cancer </li></ul></ul>
  13. 13. Other Tumor associated antigens <ul><li>Differentiation Ags: B cells produce surface Ig. B cell tumors have sIg </li></ul><ul><li>Melanomas and melanocytes express MART-1 </li></ul><ul><li>Overexpression of Ag on tumors compared to normal cells e.g. In breast cancer, HER2/neu </li></ul><ul><li>Ags expressed on male germ cells and melanoma e.g. MAGE-1 </li></ul>
  14. 14. Syngeneic (accepted) Allogeneic (rejected) Inbred : repeated brother-sister matings Outbred : normal population Xenogeneic (rejected) Tumor Growth Across Species Rat Mouse
  15. 15. How does a tumor escape immune surveillance? <ul><li>Generation of Regulatory cells (CD4 + CD25 + FoxP3 + T cells) or Myeloid-derived suppressor cells(Gr-1 + CD11b + ) </li></ul><ul><li>Secrete immunosuppressive molecules Ex: Transforming growth factor beta (TGF-  ), interleukin-10 (IL-10), etc. </li></ul>T regs MDSC CTL IL-10, etc Tumor
  16. 16. <ul><li>Failure to process and present tumor Ag. </li></ul>tumor Macrophage T helper (Th) cell B cell Cytotoxic T lymphocyte (CTL) tumor Ag tumor tumor MHC Class I MHC Class II
  17. 17. Tumors escape the action of CTL by not expressing B7 which provides 2 nd signal involved in T cell activation <ul><li>Tumors may fail to express costimulatory </li></ul><ul><li>molecules involved in T cell activation. </li></ul>tumor CTL tumor Ag Class I MHC B7 CD28
  18. 18. <ul><li>Downregulation of MHC expression on tumor cell (CTL resistant but NK sensitive) </li></ul>NK cell Tumor cell
  19. 19. Tumor escape mechanisms: Fas FasL Tumor CTL Fas FasL Tumor CTL When tumor cells express Fas Ligand, they can kill Fas + T cells, thereby escaping immune destruction.
  20. 20. Surgery Radiation Chemotherapy <ul><li>Localized tumors Metastastic tumors Affects proliferating cells </li></ul><ul><ul><li>(bone marrow, etc.) </li></ul></ul><ul><ul><li>Radiation/Drug-resistant tumors </li></ul></ul><ul><ul><li>Novel Mode: Immunotherapy </li></ul></ul>Traditional approaches to treat cancer
  21. 21. Immunotherapy <ul><li>Active Immunization : The host actively elicits an immune response. </li></ul><ul><ul><li>Specific </li></ul></ul><ul><ul><ul><li>Vaccination with viral Ags: e.g. </li></ul></ul></ul><ul><ul><ul><ul><li>Hepatitis B virus </li></ul></ul></ul></ul><ul><ul><ul><ul><li>Human Papilloma virus (HPV) - Gardasil </li></ul></ul></ul></ul>
  22. 22. <ul><li>Nonspecific : </li></ul><ul><ul><li>BCG (Bacillus Calmette-Guerin) Mycobacteria - melanoma, bladder carcinoma </li></ul></ul>Normal M  Tumor Activated M  Tumor lysis
  23. 23. <ul><li>Passive Immunization : Preformed Abs or immune cells transferred </li></ul><ul><ul><li>Specific: Ab Therapy </li></ul></ul><ul><ul><ul><li>Abs against growth factor receptor e.g. IL-2R in HTLV-1 induced Adult T cell leukemia </li></ul></ul></ul><ul><ul><ul><li>Abs specific for oncogene product e.g. Abs against HER2/ neu ( Herceptin or trastuzumab) </li></ul></ul></ul>IL-2R IL-2 Anti-IL-2R
  24. 24. Monoclonal Abs used in Immunotherapy <ul><li>Unlabelled Ab: e.g. Anti-CD20 Ab in non-Hodgkin’s lymphoma </li></ul><ul><ul><li>Complement (C’) </li></ul></ul><ul><ul><li>Ab-dependent cell mediated cytotoxicity (ADCC) </li></ul></ul><ul><li>Labelled Ab (Radioisotope/Toxin) </li></ul><ul><ul><li>131 I (Iodine) </li></ul></ul><ul><ul><li>Internalization </li></ul></ul>B cell tumor C’ M  /NK/ PMN CD20 FcR
  25. 25. <ul><li>Anti-tumor Abs coupled to toxin, radioisotopes, drugs or enzymes : </li></ul><ul><li>Immunotoxins : </li></ul><ul><li>Ricin A/diphtheria/Pseudomonas toxin coupled to Abs. e.g. antiCD20-Pseudomonas toxin in B cell leukemia </li></ul><ul><li>Internalized toxin inhibits protein synthesis. </li></ul><ul><li>Cytocidal isotopes or anticancer drugs (adriamycin) coupled to Abs </li></ul>Tumor Ricin
  26. 26. Adoptive Immunotherapy 1. Lymphokine-activated killer cells (LAK): Peripheral Blood Lymphocyte (PBL) + high dose IL-2 NK/T LAK 2. Tumor-infiltrating lymphocytes (TIL): In and around solid tumors Activated NK and CTL
  27. 27. 1)Use of LAK cells + IL-2 to treat cancer Isolate lymphocytes from blood lymphocytes +IL-2 for 3 days IL-2 LAK cells melanoma
  28. 28. Treatment of Melanoma with LAK cells +IL-2 Before After
  29. 29. 2) Use of tumor-infiltrating lymphocytes + IL-2 to treat cancer surgical removal of cancer nodule tumor T cell +IL-2 IL-2 Successful treatment of melanoma and renal cell carcinoma
  30. 30. Treatment of Melanomas with TIL + IL-2 Before After
  31. 31. Dendritic Cells <ul><li>Highly potent antigen processing and presenting cells </li></ul><ul><li>Prime an Immune Response </li></ul><ul><li>Pulse with tumor Ags or gene transfer </li></ul>Cl II Cl I
  32. 32. <ul><li>Autologous bone marrow (treated in vitro with Ab + C’) transplantation following irradiation/chemotherapy. </li></ul><ul><li>Allogeneic bone marrow transplantation (matched for HLA Ag) – Graft versus host reaction </li></ul>
  33. 33. Cytokine Therapy Inject cytokines. 1. Interleukin -2 (IL-2) high dose - Alone or with cells Melanoma and renal cell carcinoma Activates NK and CTL Toxic - fever, edema, shock 2. Tumor necrosis factor (TNF-  ) - Carcinoma
  34. 34. 3. Interferon (IFN)-  Activates NK activity Hairy B cell leukemia, renal cell carcinoma, melanoma, Kaposi sarcoma, hematologic cancers 4. IFN-  : Increases Cl II MHC expression. Ovarian carcinoma 5. Hematopoietic growth factors: Overcome neutropenia Granulocyte-macrophage colony stimulating factor (GM-CSF)
  35. 35. Gene therapy Introduce cytokine genes for IL-2, IL-4, IL-12, IFN-  or GM-CSF into tumor cells. tumor T cell M  IL-2 GM-CSF
  36. 36. SUMMARY <ul><li>Tumors should express TSTA. </li></ul><ul><li>Th cells and CTL are important in tumor rejection. </li></ul><ul><li>NK cells and macrophages also play an important role. </li></ul><ul><li>Tumors evade immune system in a number of ways. </li></ul><ul><li>Immunotherapy is promising. </li></ul>
  37. 37. Reading Immunology By Male, Brostoff, Roth and Roitt 7 th Edition Pages 401-419