Tumour immunology Prof M.I.N. Matee
Objectives <ul><li>Definition of cancer, carcinogenesis </li></ul><ul><li>Tumor antigens </li></ul><ul><li>Immune response...
Definitions of Cancer and Carcinogenesis <ul><li>Cancers consist of  single clones or several clones of cells that are cap...
<ul><li>The essence of carcinogenesis is the activation (deregulation) of genes that regulate cell growth via bypassing th...
Classification of cancer <ul><li>Carcinomas:  epithelial origin involving the skin, mucous membranes, epithlial cells in g...
Carcinogens <ul><li>Radiation:  Ultraviolet light, sunshine; X-rays, radioactive elements induce DNA damage and chromosome...
Tumor   Immunology <ul><li>evidence for immune reactivity against tumor </li></ul><ul><li>changes in cellular characterist...
Tumors stimulate an immune response <ul><li>Animals can be immunized against tumors </li></ul><ul><li>Immunity is transfer...
Oncogenesis proto-oncogenes tumor suppressor genes oncogenes carcinogen results in mutation dysfunctional  tumor suppresso...
Tumor Associated Antigens <ul><li>Human Chorionic Gonadotropin (HCG) </li></ul><ul><li>Alpha Fetoprotein (AFP)  </li></ul>...
Four mechanisms of oncogene activity to deregulate cell division
A closer look at p53
Cancer cells are different <ul><li>Escape normal intercellular communication </li></ul><ul><li>Allow for rapid growth </li...
EXPERIMENTAL EVIDENCE FOR TUMOR ANTIGENS AND IMMUNE RESPONSE
TUMOR OVEREXPRESSION OF NORMAL AG
Immunity against tumor All components, specific and nonspecific, humoral and cellular affect tumor progression and growth
Tumor Surveillance <ul><li>Macrophage/Dendritic cell attack or antigen presentation </li></ul><ul><li>CD8 cell-mediated cy...
Tumors can both activate and suppress immunity Tumors can activate the immune response (ex. expression of foreign antigen ...
Basic Tumor Immunosurveillance <ul><li>The presence of tumor cells and tumor antigens initiates the release of “danger” cy...
MAC  MHC II MAC T helper cell IL-2 T helper Memory cell T helper effectorcell IL-1 Interferon Macrophages and dendritic ce...
MAC or B cell (APC) MHC 1 T cytotoxic cell Perforins, apoptotic signals Exogenous antigen T cytotoxic memory cells T cytot...
MAC  MHC II MHC I APC T helper cell T helper 2 cell IL-2 B Cell  Eosinophil  IL-4 IL-5 T helper Memory cell T helper Effec...
TARGET CELL Y Y MAC OR NK Antibody-dependent cell-mediated cytotoxicity (ADCC)  Y
NATURAL KILLER CELL Do not recognize tumor cell via antigen specific cell surface receptor, but rather through receptors t...
Tumor surveillance by NK Cells Tumor cells produce reactive oxygen species and stress induced ligands that can be recogniz...
Tumor Escape Mechanisms <ul><li>Low immunogenicity </li></ul><ul><li>Antigen modulation </li></ul><ul><li>Immune suppressi...
Lack of MHCI as a tumor escape mechanism Defects in mechanisms of MHCI production can render cancer cells “invisible” to C...
Tumors can escape immunity (and immunotherapy) by selecting for resistant clones that have occurred due to genetic instabi...
Immunoediting of cancer cells Elimination  refers to effective immune surveillance for clones that express TSA Equilibrium...
1) Tumor cell production of immune suppressants such as   TGF-  ,  2) T regulatory cell stimulation with production of   ...
Tumor cells induce apoptosis in T lymphocytes via FAS activation <ul><li>Cancer cells express FAS ligand </li></ul><ul><li...
Issues in Immunocompetence and Cancer <ul><li>Immunosuppression is a risk for cancer </li></ul><ul><li>Cancer induces immu...
Approaches to Cancer Immunotherapy <ul><li>Cytokine manipulations </li></ul><ul><li>Tumor vaccines </li></ul><ul><li>Serot...
Cytokines <ul><li>High Toxicity </li></ul><ul><li>IL-2 </li></ul><ul><li>TNF- α </li></ul><ul><li>Interferons </li></ul>
Tumor Vaccines <ul><li>Killed tumor cells </li></ul><ul><li>Purified tumor antigens </li></ul><ul><li>DNA vaccines </li></...
<ul><li>Tumor cells can avoid activating innate responses by producing inhibitory cytokines and down-regulating or secreti...
DNA vaccination with antigen expressed on MHC
DNA vaccine (viral vector) to induce costimulatory factors and cytokines
Dendritic cell vaccine  –  dendritic cells undergo viral transduction of more effectively present antigen
SEROTHERAPY: Monoclonal Antibodies To Tumor Antigens
Additional mechanisms of antitumor activity with monoclonal antibodies <ul><li>Stimulate apoptosis via binding to Fas liga...
TUMOR ESCAPE MECHANISMS T regulatory cells Or kill them Or T regulatory cells
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Tumour immunology leture notes

  1. 1. Tumour immunology Prof M.I.N. Matee
  2. 2. Objectives <ul><li>Definition of cancer, carcinogenesis </li></ul><ul><li>Tumor antigens </li></ul><ul><li>Immune response to cancer </li></ul><ul><li>Escape mechanisms of antigenic tumors </li></ul><ul><li>Clinical tumor immunology </li></ul>
  3. 3. Definitions of Cancer and Carcinogenesis <ul><li>Cancers consist of single clones or several clones of cells that are capable of partially (benign tumor) or fully (malignant cancer) independent growth in the host. </li></ul><ul><li>Cancer cells arise from host cells via neoplastic transformation or carcinogenesis. </li></ul>
  4. 4. <ul><li>The essence of carcinogenesis is the activation (deregulation) of genes that regulate cell growth via bypassing the host’s regulatory circuits. </li></ul><ul><li>Multiple genes must be deregulated for the development of fully malignant tumors </li></ul><ul><li>Physical, chemical and biological agents may cause cancer. </li></ul>
  5. 5. Classification of cancer <ul><li>Carcinomas: epithelial origin involving the skin, mucous membranes, epithlial cells in glands </li></ul><ul><li>Sarcomas: cancer of connective tissue. </li></ul><ul><li>Lymphomas: T- B-cell, Hodgkin’s, Burkitt’s lymhomas; - solid tumors </li></ul><ul><li>Leukemias: disseminated tumors - may be lymphoid, myeloid, acute and chronic . </li></ul>
  6. 6. Carcinogens <ul><li>Radiation: Ultraviolet light, sunshine; X-rays, radioactive elements induce DNA damage and chromosome brakes. </li></ul><ul><li>Chemical: smoke and tar, countless chemicals that damage DNA (mutagens) </li></ul><ul><li>Oncogenic viruses: insert DNA or cDNA copies of viral (v) oncogens into the genome of host target cells. </li></ul><ul><li>Hereditary: certain oncogenes are inheritable. </li></ul>
  7. 7. Tumor Immunology <ul><li>evidence for immune reactivity against tumor </li></ul><ul><li>changes in cellular characteristics due to malignancy </li></ul><ul><li>tumor and host components which affect tumor progression </li></ul><ul><li>use of tumor antigens in diagnosis and immunotherapy </li></ul>
  8. 8. Tumors stimulate an immune response <ul><li>Animals can be immunized against tumors </li></ul><ul><li>Immunity is transferable from immune to naïve animals </li></ul><ul><li>Tumor specific antibodies and cell have been detected in humans with some malignancies </li></ul>
  9. 9. Oncogenesis proto-oncogenes tumor suppressor genes oncogenes carcinogen results in mutation dysfunctional tumor suppressor genes inherited defect increased GF increased GF receptors exaggerated response to GF loss of ability to repair damaged cells or induce apoptosis
  10. 10. Tumor Associated Antigens <ul><li>Human Chorionic Gonadotropin (HCG) </li></ul><ul><li>Alpha Fetoprotein (AFP) </li></ul><ul><li>Prostate Specific Antigen (PSA) </li></ul><ul><li>Mucin CA 125 (glycoprotein molecules on both normal epithelium and carcinomas) </li></ul><ul><li>Carcinoembryonic Antigen (CEA) </li></ul>
  11. 11. Four mechanisms of oncogene activity to deregulate cell division
  12. 12. A closer look at p53
  13. 13. Cancer cells are different <ul><li>Escape normal intercellular communication </li></ul><ul><li>Allow for rapid growth </li></ul><ul><li>Increased mobility of cells </li></ul><ul><li>Invade tissues </li></ul><ul><li>Metastasis </li></ul><ul><li>Evade the immune system </li></ul>
  14. 14. EXPERIMENTAL EVIDENCE FOR TUMOR ANTIGENS AND IMMUNE RESPONSE
  15. 15. TUMOR OVEREXPRESSION OF NORMAL AG
  16. 16. Immunity against tumor All components, specific and nonspecific, humoral and cellular affect tumor progression and growth
  17. 17. Tumor Surveillance <ul><li>Macrophage/Dendritic cell attack or antigen presentation </li></ul><ul><li>CD8 cell-mediated cytotoxicity </li></ul><ul><li>Antibody dependent cell mediated cytotoxicity (ADCC) </li></ul><ul><li>Natural killer cells </li></ul>
  18. 18. Tumors can both activate and suppress immunity Tumors can activate the immune response (ex. expression of foreign antigen with MHCI) or suppress the immune response (activation of T regulatory cells that release IL-10 and TGF  ) – the balance determines whether the cancer becomes clinically relevant or not Khong, H. T. et al. Nature Immunology 3, 999 - 1005 (2002)
  19. 19. Basic Tumor Immunosurveillance <ul><li>The presence of tumor cells and tumor antigens initiates the release of “danger” cytokines such as IFN  and heat shock proteins (HSP). </li></ul><ul><li>These cause the activation and maturation of dendritic cells such that the present tumor antigens to CD8 and CD4 cells </li></ul><ul><li>subsequent T cytotoxic destruction of the tumor cells the occurs </li></ul>
  20. 20. MAC MHC II MAC T helper cell IL-2 T helper Memory cell T helper effectorcell IL-1 Interferon Macrophages and dendritic cells can directly attack tumor cells, or more commonly can express exogenous antigens (TSA’s or bits of killed tumor cells) to CD4 cells Tumor cell or tumor derived antigen Dendritic and Macrophage Presentation of Tumor Antigen to CD4 Cells
  21. 21. MAC or B cell (APC) MHC 1 T cytotoxic cell Perforins, apoptotic signals Exogenous antigen T cytotoxic memory cells T cytotoxic effector cells T Cytotoxic Cell Activity in Tumor Surveillance Cancer Cell T cytotoxic cell Endogenous antigen
  22. 22. MAC MHC II MHC I APC T helper cell T helper 2 cell IL-2 B Cell Eosinophil IL-4 IL-5 T helper Memory cell T helper Effectorcell IL-1 T cytotoxic cell T cytotoxic memory cells T cytotoxic effector cells Perforins, apoptotic signals Interferon 1 Cancer Cell T cytotoxic cell Endogenous antigen Perforins, apoptotic signals Generally ineffective tumor surveillance, but some ADCC Tumor antigen or tumor cell SUMMARY
  23. 23. TARGET CELL Y Y MAC OR NK Antibody-dependent cell-mediated cytotoxicity (ADCC) Y
  24. 24. NATURAL KILLER CELL Do not recognize tumor cell via antigen specific cell surface receptor, but rather through receptors that recognize loss of expression of MHC I molecules, therefore detect “missing self” common in cancer. NK Target cell (infected or cancerous) Perforin and enzymes killer activating receptor
  25. 25. Tumor surveillance by NK Cells Tumor cells produce reactive oxygen species and stress induced ligands that can be recognized by NK cells
  26. 26. Tumor Escape Mechanisms <ul><li>Low immunogenicity </li></ul><ul><li>Antigen modulation </li></ul><ul><li>Immune suppression by tumor cells or T regulatory cells </li></ul><ul><li>Induction of lymphocyte apoptosis </li></ul>
  27. 27. Lack of MHCI as a tumor escape mechanism Defects in mechanisms of MHCI production can render cancer cells “invisible” to CD8 cells
  28. 28. Tumors can escape immunity (and immunotherapy) by selecting for resistant clones that have occurred due to genetic instability
  29. 29. Immunoediting of cancer cells Elimination refers to effective immune surveillance for clones that express TSA Equilibrium refers to the selection for resistant clones (red) Escape refers to the rapid proliferation of resistant clones in the immunocompetent host
  30. 30. 1) Tumor cell production of immune suppressants such as TGF-  , 2) T regulatory cell stimulation with production of immune suppressants such as TGF-  1 2 Avoidance of tumor surveillance through release of immune suppressants Mapara Journal of Clinical Oncology. 22(6):1136-51, 2004
  31. 31. Tumor cells induce apoptosis in T lymphocytes via FAS activation <ul><li>Cancer cells express FAS ligand </li></ul><ul><li>Bind to FAS receptor on T lymphocytes leading to apoptosis </li></ul>
  32. 32. Issues in Immunocompetence and Cancer <ul><li>Immunosuppression is a risk for cancer </li></ul><ul><li>Cancer induces immunosuppression </li></ul>
  33. 33. Approaches to Cancer Immunotherapy <ul><li>Cytokine manipulations </li></ul><ul><li>Tumor vaccines </li></ul><ul><li>Serotherapy </li></ul><ul><li>Adoptive immunotherapy </li></ul>
  34. 34. Cytokines <ul><li>High Toxicity </li></ul><ul><li>IL-2 </li></ul><ul><li>TNF- α </li></ul><ul><li>Interferons </li></ul>
  35. 35. Tumor Vaccines <ul><li>Killed tumor cells </li></ul><ul><li>Purified tumor antigens </li></ul><ul><li>DNA vaccines </li></ul><ul><li>Dendritic cell vaccines </li></ul>
  36. 36. <ul><li>Tumor cells can avoid activating innate responses by producing inhibitory cytokines and down-regulating or secreting ligands for activating receptors. M , macrophage; TCR, T cell receptor. </li></ul><ul><li>(B) Activation of innate responses can be enhanced by administering adjuvants, ligands for costimulatory proteins, cytokines, or drugs that directly trigger innate immune cells. GalCer, -galactosylceramide. </li></ul>Turning on the immune response to tumor cells through administration of immune stimulants
  37. 37. DNA vaccination with antigen expressed on MHC
  38. 38. DNA vaccine (viral vector) to induce costimulatory factors and cytokines
  39. 39. Dendritic cell vaccine – dendritic cells undergo viral transduction of more effectively present antigen
  40. 40. SEROTHERAPY: Monoclonal Antibodies To Tumor Antigens
  41. 41. Additional mechanisms of antitumor activity with monoclonal antibodies <ul><li>Stimulate apoptosis via binding to Fas ligand (Caspase pathway); </li></ul><ul><li>Antibody- dependent cell mediated cytotoxicity; </li></ul><ul><li>Bind complement </li></ul>
  42. 42. TUMOR ESCAPE MECHANISMS T regulatory cells Or kill them Or T regulatory cells

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