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  1. 1. Tumor <ul><li>A tumor is a local growth of abnormal tissue consisting of genetic-altered transformed cells and a number of other cell types and connective tissue components characteristic of each tumor type. </li></ul>
  2. 2. A fight between immune cells and cancer But, sometimes we lose
  3. 3. How does cancer arise? II <ul><li>Q: What causes dysregulated cell growth & proliferation? </li></ul><ul><li>Intrinsic factors - Genetic mutations on Oncogenes & Tumor suppressor genes </li></ul><ul><li>Environmental factors – Radiation, Carcinogens </li></ul><ul><li>Microbial infections – Viruses (viral oncogenes) </li></ul><ul><li> Bacteria </li></ul>
  4. 4. How do cancer cells differ from normal? <ul><li>Clonal in origin </li></ul><ul><li>Deregulated growth and lifespan </li></ul><ul><li>Altered tissue affinity </li></ul><ul><li>Resistance to control via apoptotic signals </li></ul><ul><li>Change in surface phenotype and markers </li></ul><ul><li>Structural and biochemical changes </li></ul><ul><li>Presence of tumour-specific antigens </li></ul>
  5. 5. Molecular Basis of Cancer Uncontrolled cell growth <ul><li>Conversion of proto-oncogenes to oncogenes: </li></ul><ul><li>amplification of c-erbB2 in breast cancer </li></ul><ul><li>point mutation of c-ras in kidney and bladder cancers </li></ul><ul><li>chromosome translocation of c-myc in Burkitt’s lymphoma </li></ul><ul><li>Altered tumor-suppressor genes: </li></ul><ul><li>P53 mutation in prostate cancer: failure in cell cycle arrest or apoptosis of prostate tumors </li></ul><ul><li>Rb mutation: fail to prevent mitosis </li></ul>
  6. 6. Cell Growth Control of cell growth Growth-promoting Proto-oncogenes Growth-restricting Tumor-suppressor genes
  7. 7. Tumor Immunology <ul><li>Cancer immunosurveilance: </li></ul><ul><li>immune system can recognize and destroy nascent transformed cells </li></ul><ul><li>Cancer immunoediting: </li></ul><ul><li>immune system kill and also induce changes in the tumor resulting in tumor escape and recurrence (epigenetic changes or Darwinian selection) </li></ul>
  8. 8. Discovery of Immune surveillance of tumors 1. Immune Surveillance- Macfarlane Burnet in 1950s 2. Use syngeneic mouse strain => Transplantation exp 3 . Immunization w/ irradiated tumor X cells protects a syngeneic mouse w/ live X tumor cells but not Y tumor cells. 4 . Antigens expressed by tumors, termed tumor antigens. 5. Defense against tumors is mainly mediated by T cells
  9. 9. Key Concepts in Tumor immunity 1. Tumors express Ags that are recognized as foreign by the host immune system. 2. Immune responses frequently fail to prevent the growth of tumors. 3. The immune system can be activated by external stimuli to effectively kill tumor cells and eradicate tumors. 4. Various strategies have been developing to enhance the anti-tumor immune responses.
  10. 10. Immune Recognition of Tumor <ul><li>Antibodies recognize intact antigens while T cells recognize processed antigens associated with MHC </li></ul>
  11. 11. Examples of tumor antigens -I
  12. 12. Examples of tumor antigens -II
  13. 13. Tumor antigens arise by point mutations in self proteins
  14. 14. Tumor antigens arise by reactivated genes or overexpressed genes
  15. 15. Immune responses to tumors 1. Adaptive immune responses to tumors: a. CD8 CTLs are the key players on the killing effect of tumors. b. CD4 T helper cells => cytokines => CTLs c. Abs => activating complements or Ab-dep cell-med toxicity => preventing oncogenic viruses 2. Innate immune responses to tumors: a. NK cells kill many types of tumor cells that have reduced class-I but express ligands for activating NK cells. b. Macrophages => Ab-med phagocytosis => Cytokines (TNF-a), ROS, & NO
  16. 16. I nduction of T cell responses to tumor s Cross-priming (cross-presentation) mediated by APCs, ex. DCs
  17. 17. Direct CTL / NK attack TUMOUR CELL Fas (CD95) FasL TCR Class I + Ag Perforin Granzyme B CTL
  18. 18. Antigen-specific tumor killing: B cells (opsinization & ADCC) Tumor Complement Macrophage/ opsinization FcR Fab Fc NK cells & ADCC sIg Tumor
  19. 19. Antigen-specific Tumor Killing: T Cells MHCI peptide Apoptosis T cell receptor (TCR) Tumor IFN-  Granzyme B CD8
  20. 20. Q: Why tumors still develop in the body if the immune system has the ability to recognize them? <ul><li>Tumors develop many ways to escape </li></ul><ul><li>from immune attacks </li></ul>
  21. 21. Tumor and activated T cells Two major pathways for TCL: Fas-mediated and perforrin-mediated
  22. 22. Mechanisms of Tumor evasion Tumors w/Fas Treg infiltrating
  23. 23. Down regulation of the MHC class presentation pathway <ul><li>Downregulation of MHC class I expression is frequently seen in human tumors. </li></ul><ul><li>Loss of MHC-I as a mechanism for tumor escape from CTL-mediated elimination (longitudinal study of melanoma patients) </li></ul><ul><li>Five major HLA altered phenotypes found in tumor tissues (Human Immunol. 2000, 61:65) </li></ul>
  24. 24. The five altered phenotypes <ul><li>Normal A1A2B8B35Cw7Cw4 </li></ul><ul><li>1. Total loss - </li></ul><ul><li>2. Haplotype loss A1B8Cw7 </li></ul><ul><li>3. Locus loss A1A2B8B35 </li></ul><ul><li>4. Allelic loss A2B8B35Cw7Cw4 </li></ul><ul><li>5. Compound </li></ul><ul><li>phenotype A1 </li></ul>(Human Immunol. 2000, 61:65)
  25. 25. Resistance to killing <ul><li>Defective Fas pathway </li></ul><ul><li>Resistance to Granzyme B </li></ul><ul><li>Fas-L and Neutrophil </li></ul>Cytotoxic T cells Innate immunity
  26. 26. Three Es of Immunoediting CTL CTL NKT NK CD4 NK CTL CD4 NK CTL Elimination Equilibrium Escape Genetic instability / tumour heterogeneity
  27. 27. Immunoediting of Cancer
  28. 29. How does MM evade the immune response? myeloma cancer cell Broken up to release antigens APC APC recruits CTL specific for myeloma Ag T T T T T T cells recognise and destroy other cancer cells MM cell release factors which ‘turn off’ T cells
  29. 30. The Strategies for Cancer Therapy <ul><li>The best scenario – Kill all the tumor cells without destroy others in the body </li></ul><ul><li>Surgery – remove tumor cells & tissues physically </li></ul><ul><li>Radiotherapy – non-selective, strong side effect </li></ul><ul><li>Chemotherapy - non-selective, strong side effect </li></ul><ul><li>Gene therapy – relatively selective </li></ul><ul><li>Targeted therapy - relatively selective </li></ul><ul><li>Immunotherapy => manipulate an immune response against tumor cells but not normal cells </li></ul><ul><li>=> quite selective </li></ul>
  30. 31. Tumor vaccines-Targeting DCs
  31. 32. Types of Tumor Vaccines
  32. 33. Immunotherapy with cytokine gene-transfected tumor cells
  33. 34. Systemic cytokine therapy for tumors
  34. 35. Passive Immunotherapy for tumors Adoptive cellular therapy
  35. 36. Therapy with Anti-tumor Monoclonal Abs
  36. 37. Approved Anti-tumor mAb
  37. 38. SUMMARY 1. Cancer is a complex and progressive genetic disease. 2. Tumors express Ags that could be recognized by the immune system. But some tumors are weakly immunogenic and the immune system often fails to eradicate them. 3. Cancer from clinical cases usually represents the leading of cancer development over the anti-cancer immune responses. 4. The imperative issue in the field of tumor immunology is to improve the capability of immune defenses to fight cancer.