Cancer immunology.pptx

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1. Cancer immunology -

2. “swelling”) results from ABNORMAL PROLIFERATION of cells, through the loss or Cancer remains one of the leading causes of death globally, with an estimated 12.7 million cases around the world affecting both sexes equally. This number is expected to increase to 21 million by 2030. Appearance of a tumor (from the Latin word for modification of normal growth control. Cells which normally do not divide (e.g. muscle or kidney cells) may start proliferating, or cells which normally do proliferate (e.g. basal epithelial cells or hemopoeitic cells) may begin dividing in an uncontrolled fashion. Cancer

3. Carcinogens Radiation : Ultraviolet light, sunshine; X-rays, radioactive elements induce DNA damage and chromosome breaks. Chemical : smoke and tar, countless chemicals that damage DNA (mutagens). Oncogenic viruses : insert DNA or cDNA copies of viral oncogens into the genome of host target cells. Hereditary : certain oncogenes are inheritable.

4. Classification of cancer Carcinomas : epithelial origin involving the skin, mucous membranes, epithelial cells in glands Sarcomas : cancer of connective tissue. Lymphomas : T- B-cell, Hodgkin’s, Burkitt’s lymhomas; - solid tumors Leukemias : disseminated tumors - may be lymphoid, myeloid, acute and chronic .

5. Tumor Immunology Tumor antigens Effectors mechanisms in anti-tumor immunity Mechanisms of tumor evasion of the Immune system Immunotherapy for tumors

6. Tumor Antigen Many tumors can be shown to express cell surface antigens which are not expressed in the normal progenitor cells before the neoplastic transformation event. These antigens have been categorized based on their nature and distribution, resulting in a complex collection of acronyms, some of which are defined as:

7. Tumor Antigen T um o r -S p e c if i c T ran s pl a n t a t i o n Ant i gen s , o r TS T A Chemical or radiation-induced tumors each generally express a unique neo-antigen, different from other tumors induced by the same or different agent. T um o r -Ass o ciated T ran s pl a n t a t i o n Ant i gen s , o r TATA Tumors induced by the same virus express antigens shared between different tumors. These consist of membrane-expressed virally encoded antigens, and have been termed Tumor-Associated Transplantation Antigens (since they are not, strictly speaking, tumor “specific”).

8. Tumor Antigen 3. Oncofetal antigens: These are TATAs which are more or less selectively expressed on tumors, but are also shared with some normal fetal or embryonic tissues. Examples include carcinoembryonic antigen (CEA, shared with healthy fetal gut tissue), and alpha- fetoprotein (AFP, also present in the serum of healthy infants, but decreasing by one year of age).

9. Tumors stimulate an immune response Animals can be immunized against tumors Immunity is transferable from immune to naïve animals Tumor specific antibodies and cell have been detected in humans with some malignancies

10. proto-oncogenes tumor suppr essor genes oncogenes carcinogen results in mutation dysfunctional tumor suppressor genes inher i ted defect increased GF increased GF receptors exaggerated response to GF loss of ability to repair damaged cells or induce apoptosis

11. Four mechanisms of oncogene activity to deregulate cell division

12. ⦿ Escape normal intercellular communication ⦿ Allow for rapid growth ⦿ Increased mobility of cells ⦿ Invade tissues ⦿ Metastasis ⦿ Evade the immune system 12

13. EXPERIMENTAL EVIDENCE FOR TUMOR ANTIGENS AND IMMUNE RESPONSE

14. Immunosurveillance An hypothesis that states that a physiologic function of the immune system is to recognize and destroy malignantly transformed cells before they grow into tumors. Implies that cells of the immune system recognize something “foreign” on transformed/tumor cells.

15. Immune Surveillance of Tumors Normal cell Transformed (cancerous) but also antigenic Mutation or virus Transformed (cancerous) but escapes from immune response Immune r e sponse Dead Mut a t i on Analogous to a bacterial population being treated with antibiotics such that antibiotics resistant mutants take over the population

16. ⦿ Macrophage/Dendritic cell attack or antigen presentation ⦿ CD8 cel l -m e d i a t ed cytot o xicity ⦿ Ant i b o dy d e p e n d e n t cell m e di a ted cytotoxicity (ADCC) ⦿ Nat u ral killer cells

17. 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.

18. Basic Tumor Immunosurveillance The presence of tumor cells and tumor antigens initiates the release of “danger” cytokines such as IFN  and heat shock proteins (HSP). These cause the activation and maturation of dendritic cells such that they present tumor antigens to CD8 and CD4 cells subsequent T cytotoxic destruction of the tumor cells occurs

19. Helper T cells CD4+ T cells: reacting to class II MHC peptide complex, they secret cytokines. cytotoxic T cell response (Th1 helper T cells) antibody response (Th2 helper T cells) Dendritic Cells The professional antigen-presenting cells In the final common pathway for activating naïveTcells.

20. AC MHC II M MAC T helper cell I L -2 T helper M em o r y cell T helper effect o r cell I L - 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 T umor c e ll or tumor derived antigen Dendritic and Macrophage Presentation of Tumor Antigen to CD4 Cells

21. Cytotoxic T cells (CTLs)T cells(CTLs) CD8+ T cells: attaching to class I MHC peptide complex, they destroy cancer cells by perforating the membrane with enzymes or by triggering an apoptotic pathway.

22. 22 MAC or B cell (APC) MHC 1 T cytotoxic cell Perforins, apoptotic signals E x ogenous antigen T cytotoxi c m e m o ry cells T c y t o t o xic effector cells T Cytotoxic Cell Activity in Tumor Sur v eillanc e Cancer Cell T c y t o t o xic cell Endo ge nous antigen

23. C y t ok i n e s Regulating the innate immune system: NK cells, macrophages and neutrophils; and the adaptive immune system: T and B cells IFN- α-- upregulating MHC class I tumor antigens and adhesion molecules; promoting activity of B and T cells, macrophages, and dendritic cells. IL-2-- T cell growth factor that binds to a specific tripartite receptor on T cells. IL- 12 – promoting NK and T cell activity and a growth factor for B cells GM-CSF(Granulocyte-monocyte colony stimuating factor) -- reconstituting antigen-presenting cells

24. Antibody - produced by B cells Direct attack : blocking growth factor receptors, arresting proliferation of tumor cells, or inducing apoptosis. -- is not usually sufficient to completely protect the bo dy. Indirect attack : -- major protective efforts ADCC(antibody-dependent cell mediated cytotoxicity) -- recruiting cells that have cytotoxicity, such as monocytes and macrophages . CDC (complement dependent cytotoxicity) -- binding to receptor, initiating the complement system, 'complement cascade’, resulting in a membrane attack complex causing cell lysis and death.

25. NK Target cell (infected or cancerous) Perforin and enzymes killer activating receptor 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.

26. ⦿ L o w i m m u n o g e n i city ⦿ Ant i g e n m o d ul a ti o n ⦿ Im m u n e sup p ression by tu m or cells or T regulatory cells ⦿ Induction of lymphocyte apoptosis

27. Defects in mechanisms of MHCI production can render cancer cells “invisible” to CD8 cells

28. Tumors can escape immunity (and immunotherapy) by selecting for resistant clones that have occurred due to genetic instability

29. 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 29

30. 1 2 Avoidance of tumor surveillance through release of immune suppressants

31. Tumor cells induce apoptosis in T lymphocytes via FAS activation Cancer cells express FAS ligand. Bind to FAS receptor on T lymphocytes leading to apoptosis.

32. Cancer Immunotherapy Immunotherapy is the most recent advanced technique in cancer therapy. Cancer Immunotherapy is the use of immune system to reject Cancer. The main purpose of this premise is stimulating the patient’s immune system to attack the malignant tumour cells that are responsible for the disease. Immunotherapy works to harness the innate powers of the immune system to fight cancer. It fights cancer more powerfully, to offer long-term protection, with less side effects. It may hold greater potential than current treatments, due to unique properties of Immune System.

33. Mo n o c lonal Antib o dies Cytokines Adoptive cell Therapy Cancer Vaccines

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