1.Tumour immunology Prof M.I.N. Matee

2. Objectives

Definition of cancer, carcinogenesis

Tumor antigens

Immune response to cancer

Escape mechanisms of antigenic tumors

Clinical tumor immunology

3. Definitions of Cancer and Carcinogenesis

Cancers consist ofsingle clones or several clones of cells that are capable of partially (benign tumor) or fully (malignant cancer) independent growth in the host.

Cancer cells arise from host cells via neoplastic transformation or carcinogenesis.

4.

The essence of carcinogenesis is the activation (deregulation) of genes that regulate cell growth via bypassing the hosts regulatory circuits.

Multiple genes must be deregulated for the development of fully malignant tumors

Physical, chemical and biological agents may cause cancer.

5. Classification of cancer

Carcinomas:epithelial origin involving the skin, mucous membranes, epithlial cells in glands

Sarcomas:cancer of connective tissue.

Lymphomas:T- B-cell, Hodgkins, Burkitts lymhomas; -solid tumors

Leukemias:disseminated tumors -may be lymphoid, myeloid, acute and chronic .

6. Carcinogens

Radiation:Ultraviolet light, sunshine; X-rays, radioactive elements induce DNA damage and chromosome brakes.

Chemical:smoke and tar, countless chemicals that damage DNA (mutagens)

Oncogenic viruses:insert DNA or cDNA copies of viral (v) oncogens into the genome of host target cells.

Hereditary:certain oncogenes are inheritable.

7. Tumor Immunology

evidence for immune reactivity against tumor

changes in cellular characteristics due to malignancy

tumor and host components which affect tumor progression

use of tumor antigens in diagnosis and immunotherapy

8. Tumors stimulate an immune response

Animals can be immunized against tumors

Immunity is transferable from immune to nave animals

Tumor specific antibodies and cell have been detected in humans with some malignancies

9. Oncogenesis proto-oncogenes tumor suppressor genes oncogenes carcinogen results in mutation dysfunctionaltumor suppressor genes inherited defect increased GF increased GF receptors exaggerated response to GF loss of ability to repair damagedcells or induce apoptosis 10. Tumor Associated Antigens

Human Chorionic Gonadotropin (HCG)

Alpha Fetoprotein (AFP)

Prostate Specific Antigen (PSA)

Mucin CA 125 (glycoprotein molecules on both normal epithelium and carcinomas)

Carcinoembryonic Antigen (CEA)

11. Four mechanisms of oncogene activity to deregulate cell division 12. A closer look at p53 13. Cancer cells are different

Escape normal intercellular communication

Allow for rapid growth

Increased mobility of cells

Invade tissues

Metastasis

Evade the immune system

14. EXPERIMENTAL EVIDENCE FOR TUMOR ANTIGENS AND IMMUNE RESPONSE 15. TUMOR OVEREXPRESSION OF NORMAL AG 16. Immunity against tumor All components, specific and nonspecific, humoral and cellular affect tumor progression and growth 17. Tumor Surveillance

Macrophage/Dendritic cell attack or antigen presentation

CD8 cell-mediated cytotoxicity

Antibody dependent cell mediated cytotoxicity (ADCC)

Natural killer cells

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 Immunology3, 999 - 1005 (2002) 19. 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 the present tumor antigens to CD8 and CD4 cells

subsequent T cytotoxic destruction of the tumor cells the occurs

20. MACMHC 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 (TSAs 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. 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. MACMHC II MHC I APC T helper cell T helper 2 cell IL-2 B CellEosinophilIL-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. TARGET CELL Y Y MAC OR NK Antibody-dependent cell-mediated cytotoxicity (ADCC)Y 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. NKTarget cell (infected or cancerous) Perforin and enzymes killer activating receptor 25. Tumor surveillance by NK Cells Tumor cells produce reactive oxygen species and stress induced ligands that can be recognized by NK cells 26. Tumor Escape Mechanisms

Low immunogenicity

Antigen modulation

Immune suppression by tumor cells or T regulatory cells

Induction of lymphocyte apoptosis

27. Lack of MHCI as a tumor escape mechanism 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. Immunoediting of cancer cells Eliminationrefers to effective immune surveillance for clones that express TSA Equilibriumrefers to the selection for resistant clones (red) Escaperefers to the rapid proliferation of resistant clones in the immunocompetent host 30. 1) Tumor cell production of immune suppressants such as TGF- ,2) T regulatory cell stimulation with production ofimmune suppressants such as TGF- 1 2 Avoidance of tumor surveillance through release of immune suppressants MaparaJournal of Clinical Oncology. 22(6):1136-51, 2004 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. Issues in Immunocompetence and Cancer

Immunosuppression is a risk for cancer

Cancer induces immunosuppression

33. Approaches to Cancer Immunotherapy

Cytokine manipulations

Tumor vaccines

Serotherapy

Adoptive immunotherapy

34. Cytokines

High Toxicity

IL-2

TNF-

Interferons

35. Tumor Vaccines

Killed tumor cells

Purified tumor antigens

DNA vaccines

Dendritic cell vaccines

36.

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.

(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.

Turning on the immune response to tumor cells through administration of immune stimulants 37. DNA vaccination with antigen expressed on MHC 38. DNA vaccine (viral vector) to induce costimulatory factors and cytokines 39. Dendritic cell vaccinedendritic cells undergo viral transduction of more effectively present antigen 40. SEROTHERAPY: Monoclonal Antibodies To Tumor Antigens 41. Additional mechanisms of antitumor activity with monoclonal antibodies

Stimulate apoptosis via binding to Fas ligand (Caspase pathway);

Antibody- dependent cell mediated cytotoxicity;

Bind complement

42. TUMOR ESCAPE MECHANISMS T regulatory cells Or kill them Or T regulatory cells