Theory of immune surveillance

Immune surveillance theory

1. By Shariqa Aisha University of Kashmir Theory of Immune Surveillance

2. Learning Objectives To Understand the concept of Immune Surveillance Theory. To acquire the knowledge regarding the Discovery of Immune Surveillance Theory. To Find out the Evidences of Immune Surveillance theory. To explore the concept of Tumor Antigens. To learn Immune Surveillance Systems. To know about the process of Immunoediting.

3. Introduction Immune surveillance theory states that the immune system patrols the body not only to recognize and destroy invading pathogens but also host cells that become cancerous. In 1909, Paul Ehrlich formulated the hypothesis that host defense may prevent neoplastic cells from developing into tumor. This hypothesis was not proven experimentally at that time due to the inadequacy of experimental tools. Paul Erlich

4. Introduction In the late 1950s, Burnett & Thomas redefined the idea into the “Immune Surveillance Hypothesis of Cancer ”. They suggested that the immune system recognize newly arising tumors through the expression of tumor specific neo-antigens on tumor cells and eliminate them, similarly to homograft rejection . Schreiber , and their colleague's demonstrated that mice with a compromised immune status were more prone than immunocompetent mice to developing, an array of cancers. The first clear demonstration of specific capability to stimulate an immune response was made by Gross in 1953 after intradermal immunization of C3H mice, obtained by continuous brother to sister mating for more 20 years, against a sarcoma, followed by Foley in 1953 in methylcholantrene-induced tumor. Lewis Thomas MacFarlane Burnet

5. Evidences Confirming The Theory Of Immune Surveillance EXPERIMENTAL EVIDENCE 1:The first experimental demonstration that tumors can induce protective immune responses came from studies of transplanted tumors . In transplantation models, tumors are rejected in syngeneic hosts, while transplantation of normal tissues are accepted, confirming the existence of tumor-specific antigens. Mice and rats of a given haplotype can be immunized with irradiated cancer cells that arose in animals of the same haplotype. when they are challenged with liver cancer cells, they are able to resist the tumor challenge. Klin made innovative observation that not only the syngeneic animals be immunized, but the primary animal that develops the tumor is also immune to subsequent challenges with the same tumor.

6. 1. Mice immunized with tumor cells are protected against subsequent tumor growth. 2. The primary animal that develops the tumor is also immune to subsequent challenges with the same tumor .

7. EXPERIMENTAL EVIDENCE 2: Mice are immunized against a given fibrosarcoma, they are rendered immune to that fibrosarcoma . The m ost extensive interrogation of the individually distinct antigenicity of chemically induced tumors was carried out by Basombrio and Prehn . They induced fibrosarcomas in 25 syngeneic BALB/c mice using methylcholanthrene and tested the immunogenicity of each one against all other tumors in an immunization-challenge mode.

8. Tumor used to challenge Tumor used to immunize A B C D A + - - - B - + - - C - - + - D - - - + + denotes tumor immunity or lack of tumor growth; -denotes lack of tumor immunity or tumor growth When mice are immunized against a given fibrosarcoma they rendered immune to that fibrosarcoma .

9. CLINICAL EVIDENCE: S everal clinical observations point to the existence of tumor protective immunity in humans. Immunosuppressed or Immunodeficient humans include the increased relative risk of cancers .( Table 1) e.g., AIDS patients and kidney transplant recipients. ( Table 2) Immunocompetent Humans contain large numbers of tumor-infiltrating lymphocytes(TILs), e.g., Th1 cells and/or cytotoxic T lymphocytes(CTLs) and/or NK cells cope up with their disease better than patients with only small no of these cells.

10. Relative risk of tumors in immunosuppressed kidney transplant Tumor type Approximate relative risk Kaposi’s sarcoma 50-100 Non-Hodgkin’s lymphoma 25-45 Carcinoma of the liver 20-35 Carcinoma of the skin 20-50 Carcinoma of cervix 2.5-10 melanoma 2.5-10 lung 1-5 Table 1

11. Tumor viruses and immunodeficiency Cause of immunodeficiency Common tumor types Viruses involved Inherited immunodeficiency lymphoma EBV Immunosuppression for organ transplants or due to AIDS Lymphoma Cervical cancer Skin cancer Liver cancer Kaposi’s cancer EBV Papilloma viruses Probably papilloma viruses Hepatitis B and C human herpes virus 8 malaria Burkitt’s lymphoma EBV autoimmunity lymphoma EBV Table 2

12. Tumor Antigens Tumor antigen is an antigenic substance produced in tumor cells, i.e., it triggers immune response in the host. Two types of tumor antigens have been identified on tumor cells: tumor-specific transplantation antigens (TSTAs) and tumor-associated transplantation antigens(TATAs). Tumor-specific antigens are unique to tumor cells and do not occur on normal cells in the body. They are presented with class I MHC molecules, inducing a cell-mediated response by tumor-specific CTLs. Tumor-associated antigens , are not unique to tumor cells , but are expressed on normal cells too during fetal development.

13. List of the major types of the tumor antigens

14. Immune Surveillance Systems The immune surveillance system includes: Natural killer (NK) cells: They play an important role in the immune surveillance of cancer. Fc receptors on NK cells can bind to antibody-coated tumor cells, leading to ADCC. NK cells demolished tumor through perforin and granzyme , which are important for immune surveillance and death of tumor cells induced by cytokines such as tumor necrosis factor (TNF), Fas ligand ( CD95), interferon-γ (IFN-γ) and IL-10. Macrophages show the same mechanism that of the NK cells.

15. NK cell mediated cell death of tumor cells

16. 2. Cytotoxic T- lymphocytes ( CTLs): Tumor antigen-specific cytotoxic T- lymphocytes are the major effectors in the immune surveillance against tumor cells. CD8 + T cell responses to tumors may be induced by cross-priming (also called cross-presentation ) in which the tumor cells and/or tumor antigens are taken up by professional APCs processed and presented to T cells. In some cases B7 costimulators expressed by the APCs provide the second signals for the differentiation of the CD8 + T cells . The APCs may also stimulate CD4+ helper T cells which provide the second signals for CTL development. Differentiated CTLs kill tumor cells without a requirement for costimulation or T cell help.

17. Induction of T cell responses to tumors

18. B - cells: Tumor-bearing hosts may produce antibodies against various tumor antigens. For example, patients with EBV associated lymphomas have serum antibodies against EBV-encoded antigens expressed on the surface of the lymphoma cells . Antibodies bind together on tumor cell surface leading to the destruction of tumor through: Antibody - dependent cell mediated cytotoxicity. Activation of macrophages. Activation of classical pathway of complement system.

19. Immunoediting Immunoediting that describes the transformation of normal cells to clinically-detectable cancer. The concept of Immunoediting was proposed by Gavin P. Dunn and Robert Schreiber . The immunoediting process consists of three phases, often referred to as the “3 Es”: elimination, equilibrium and escape. Elimination : In this phase, growing tumors are completely eliminated by the immune system. Both innate and adaptive cells play role in this. Equilibrium : During this phase, cancer remains clinically undetectable and is dormant. Persons whose tumors are in equilibrium may either revert to elimination or progress on to the escape phase . Escape: In this phase, cancer cells escaped the immune system. Robert Schreiber

20. Phases of Cancer Immunoediting

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