Tumor And Immunity


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Tumor And Immunity

  1. 1. Journal reading Changes in host defence induced by malignancies and antineoplastic treatment: implication for immunotherapeutic strategies 97/11/26 R2 林軒名
  2. 2. Content <ul><ul><li>Introduction </li></ul></ul><ul><ul><li>Barriers </li></ul></ul><ul><ul><li>Adaptive immunity </li></ul></ul><ul><ul><li>Cytokines </li></ul></ul>
  3. 3. Introduction Immunity Malignancy Therapy
  4. 4. Barriers <ul><ul><li>The exterior bodily defences : Mucosa </li></ul></ul><ul><ul><li>Mucositis increases the risk for infections </li></ul></ul><ul><ul><li>Current therapy: essentially palliative </li></ul></ul><ul><ul><li>Palifermin (recombinant keratinocyte growth factor, fibroblast growth factor 7), interleukin-11, interleukin-15, and granulocyte-macrophage colony-stimulating factor </li></ul></ul>
  5. 6. Innate immunity : NK cells <ul><ul><li>Deficiencies • severe infection with viral and mycobacterial pathogens . </li></ul></ul><ul><ul><li>Maintaining continuous remission for acute leukemia. </li></ul></ul><ul><ul><li>Thymoma and melanoma cells , can interrupt functional maturation of natural killer cells. </li></ul></ul><ul><ul><li>Aggressive cytotoxic regimens decrease the number of circulating natural killer cells </li></ul></ul>
  6. 7. Innate immunity : NK cells <ul><ul><li>In Rat, ketamine, thiopental, and morphine , suppress naturalkiller-cell activity </li></ul></ul><ul><ul><li>Hyperthermia increases NK cells </li></ul></ul><ul><ul><li>Natural-killer-cell-based immunotherapeutic strategies include the proliferation and activation of the cells in vivo and the combination of the cells with other treatment modalities, for example with bispecific antibodies. </li></ul></ul>
  7. 8. Innate immunity : Phagocytes <ul><ul><li>key effector cells with microbicidal capabilities. </li></ul></ul><ul><ul><li>febrile neutropenic: risk-adapted approach </li></ul></ul><ul><ul><ul><li>Expected duration and depth of neutropenia, </li></ul></ul></ul><ul><ul><ul><li>the type of underlying Malignancy </li></ul></ul></ul><ul><ul><ul><li>Clinical parameters </li></ul></ul></ul><ul><ul><ul><li>Laboratory markers such as interleukin-6 </li></ul></ul></ul><ul><ul><li>Qualitative defects of phagocytic function • increase the risk for infection </li></ul></ul>
  8. 9. Innate immunity : Phagocytes <ul><ul><li>Glucocorticosteroids </li></ul></ul><ul><ul><ul><li>Downregulate NADPH-oxidase system </li></ul></ul></ul><ul><ul><ul><li>suppress the production of various cytokines by several mechanisms, inhibition of the transcription factor nuclear factor κB(NFκB) </li></ul></ul></ul><ul><ul><ul><li>Fluorouracil, doxorubicin, and cyclophosphamide, or interleukin-2, suppressneutrophil migration </li></ul></ul></ul>
  9. 11. Innate immunity : Phagocytes <ul><ul><li>Etoposide: induces proinflammatory cytokine production </li></ul></ul><ul><ul><li>Rituximab : Induces a depletion of B cells, </li></ul></ul><ul><ul><li>Morphine: suppresses complement and Fcγ-receptor expression and neutrophil functions </li></ul></ul><ul><ul><li>G-CSF: primary prophylaxis for chemotherapy-induced febrile neutropenia: </li></ul></ul><ul><ul><li>Granulocyte transfusions : no defined benefit. </li></ul></ul>
  10. 12. Innate immunity : Dendritic cells <ul><ul><li>Antigen-presenting cells </li></ul></ul><ul><ul><li>Initiate adaptive immune responses by secreting cytokines and activating lymphocytes </li></ul></ul><ul><ul><li>Effect </li></ul></ul><ul><ul><ul><li>Number reduced : ALL or non-small-cell lung cancer (NSCLC) </li></ul></ul></ul><ul><ul><ul><li>Functional impairment : Chemo therapy for malignancy </li></ul></ul></ul>
  11. 13. Olivera J. Finn, Ph.D. Cancer Immunology , N Engl J Med 2008;358:2704-15
  12. 14. Innate immunity : Dendritic cells <ul><ul><li>Imatinib </li></ul></ul><ul><ul><ul><li>inhibitor of tyrosine kinases </li></ul></ul></ul><ul><ul><ul><li>inhibits differentiation of CD34+ progenitors into dendritic cells as well as the function of dendritic cells and monocytes </li></ul></ul></ul>
  13. 15. Innate immunity : Dendritic cells <ul><ul><li>Dendritic cells pulsed with pathogen or tumour-derived antigen(s) </li></ul></ul><ul><ul><ul><li>Example: aspergillosis, papillomavirus </li></ul></ul></ul><ul><ul><li>Imiquimod (synthetic agonist of Toll-like receptor 7), are directly involved in the destruction of basal cell carcinoma • bladder cancer. </li></ul></ul>
  14. 16. Adaptive immunity: T cells <ul><ul><li>Regulatory T cells: </li></ul></ul><ul><ul><ul><li>Suppression of both adaptive and innate immunity thus preventing autoimmunity and allograft rejection, and downregulating antimicrobial and antitumour immune responses </li></ul></ul></ul><ul><ul><ul><li>TReg cells depend on exogenous interleukin 2 </li></ul></ul></ul><ul><ul><li>CD4+ and CD8+ T cells: increase the host response against microorganisms </li></ul></ul>
  15. 17. Adaptive immunity: T cells <ul><ul><li>Rapid recovery of T cells after treatment for malignancy is associated with a better prognosis </li></ul></ul><ul><ul><li>Chronic graft-versus-host-disease have a lower incidence of relapse </li></ul></ul><ul><ul><li>Depletion of the TReg subset : augment antitumour immunity </li></ul></ul>
  16. 18. Adaptive immunity: T cells <ul><ul><li>Myeloid malignancies or Hodgkin’s disease </li></ul></ul><ul><ul><ul><li>suppressed Cell-mediated immunity </li></ul></ul></ul><ul><ul><ul><li>increased numbers of TReg cells </li></ul></ul></ul><ul><ul><ul><li>Ex: lower expression of the T-cell receptor (TCR)-zeta chain in Hodgkin’s disease; Myeloma: multiple signalling defects of T cells </li></ul></ul></ul>
  17. 19. Adaptive immunity: T cells <ul><ul><li>Cyclophosphamide : induce a profound reduction in the number of circulating TReg cells </li></ul></ul><ul><ul><li>Interleukin-2: increased number TReg cells, suppressive activity in vitro. No postive results. </li></ul></ul><ul><ul><li>Temozolomide: CD4+ lymphopenia. Induced Pneumocystis jiroveci and Aspergillus </li></ul></ul>
  18. 20. Adaptive immunity: T cells <ul><ul><li>Alemtuzumab </li></ul></ul><ul><ul><li>Imatinib mesylate </li></ul></ul><ul><ul><li>Radiotherapy : lymphocyte subpopulations </li></ul></ul><ul><ul><li>Whole-body hyperthermia: decreases peripheral numbers of T cells </li></ul></ul><ul><ul><li>Amphotericin B : negatively affect the </li></ul></ul><ul><ul><li>cytotoxic T-cell function in vivo </li></ul></ul>
  19. 21. <ul><ul><li>ALL </li></ul></ul><ul><ul><ul><li>defects in CD4+ and CD8+ T-cell numbers </li></ul></ul></ul>
  20. 22. <ul><ul><li>Donor-derived T cells (after alloPBSCT) beneficial in patients with severe viral or fungal infection or in patients with relapse of the underlying malignancy </li></ul></ul><ul><ul><li>Donor lymphocyte infusions effective, but high risk of graft versus host disease </li></ul></ul>
  21. 23. Adaptive immunity: Humoral defence mechanisms
  22. 24. Cytokines
  23. 25. Olivera J. Finn, Ph.D. Cancer Immunology , N Engl J Med 2008;358:2704-15
  24. 27. Reference <ul><ul><li>Olivera J. Finn, Ph.D. Cancer Immunology , N Engl J Med 2008;358:2704-15. </li></ul></ul><ul><ul><li>Mark J. Smyth, Ph.D. Imatinib Mesylate : Uncovering a Fast Track to Adaptive Immunity NEJM 354;21 May 25, 2006 </li></ul></ul><ul><ul><li>Glenn Dranoff, Cytokines in cancer pathogenesis and cancer therapy Nature Reviews Cancer 4, 11 - 22 (01 Jan 2004), doi: 10.1038/nrc1252, Review </li></ul></ul>