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Objectives

11. Cancer and the Immune System (มะเร็งกับระบบภูมิคุ้มกัน ). Objectives. Students should be able to explain cell-mediated immune response and immunological tolerance . Students should be able to describe how to induce tumor immunity. Contents. 11.1 Introduction.

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Objectives

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  1. 11. Cancer and the Immune System (มะเร็งกับระบบภูมิคุ้มกัน ) Objectives • Students should be able to explain cell-mediated immune responseand immunologicaltolerance. • Students should be able to describe how to induce tumor immunity. Contents 11.1 Introduction 11.2 Biology of the immune system 11.3 Tolerance and the immune system 11.4 Tumor Immunology 11.5 Induction of Tumor Immunity

  2. 11. Cancer and the immune system 11.1 Introduction • Antigens are substances, usually foreign, that are specifically recognized by receptors on the cells of the immune system. • Adaptive immunity is the antigen-specific host defense that is mounted following exposure to antigen involving lymphocytes and their products. • Innate immunity results from a collection of cells and factors that constitute the early host defense system. • Immune system has ability to respond to foreign antigen but not toself-antigen. ----> Self / Nonself – discrimination or self-tolerance • An immune response against self-antigen would result in tissue damage or autoimmunity.

  3. 11.2 Biology of the immune system 11.2.1 Adaptive Immunity • responsible for the induction of immunity and immunological memory upon exposure to foreign antigens. • T and B lymphocytes are an integral part of the adaptive immune system. • B and T lymphocytes activation is triggered by different forms of the antigen. • The antigen receptors on lymphocytes recognize small parts of proteins or peptides called “epitopes”. • B cells are triggered by membrane-bound immunoglobulin molecules (B-cell receptor; BCR) interacting with intact protein antigen. • T cells recognize peptide antigens bound to MHC molecules on the surface of antigen presenting cells (APCs) or target cells. 1) T helper (Th) cells, together with CD4, recognize peptide presented by MHC class IImolecules on APCs. 2) Cytotoxic T Lymphocytes (CTLs), together with CD8, recognize peptide presented by MHC class I molecules on APCs or target cells.

  4. BCR TCR TCR CD4 CD8 MHC II MHC I

  5. Recognition of antigen initiates an immune response. • Activated B lymphocytes proliferate and differentiate into plasma cells that secrete soluble immunoglobulin (antibody) molecules responsible for humoral (antibody-mediated) immunity. • Activated T lymphocytes are responsible for cell-mediated immunity. • Strategies for immunotherapy of cancer are directed most often to the activation of CTLs. 11.2.2 The Major Histocompatibility Complex (MHC) • 3 classes 1) Class I MHC : expressed on virtually all cells : transmembrane glycoproteins 2) Class II MHC : expressed only on APCs : transmembrane glycoproteins 3) Class III MHC : components of the complement system : some cytokines (TNF-, TNF-)

  6. Antigen processing and presentation by MHC class I and class II molecules. Chaperone

  7. In the mouse, MHC = H-2 complex : MHC class I ; H-2D, H-2K, H-2L : MHC class II; I-A, I-E • In human, MHC = HLA (human leukocyte antigen) complex : MHC class I ; HLA-A, HLA-B, HLA-C : MHC class II ; HLA-DQ, HLA-DR, HLA-DP • MHC class I generally binds endogenous peptides, whereas MHC class II generally binds exogenous peptides. • However, cross-presentation can occur wherein extracellular soluble antigen can be presented by MHC class I molecules. 11.2.3 T lymphocytes 1) Cytotoxic T lymphocytes (CTLs) - function primarily to eliminate virally infected cells. - potentially play a role in the elimination of tumor cells. - express the coreceptor CD8. - recognize peptide antigen presented by MHC class I. - secrete a pore-forming protein, “perforin” , to facilitate the delivery of enzymes (granzyme B) to target cells to activate cell death. - CTL response is desired for anti-tumor immunity.

  8. 2) T helper cells (Th cells) - function primarily to regulate other cells of the immune system by secreting a range of cytokines. - Cytokines act as growth factors for the proliferation and differentiation of antigen-triggered CD8+T cells, CD4+T cells, and B cells. - 3 types of Th cells 1) Th 1 cells:-secrete interleukin (IL)-2, interferon- (INF  ), and granulocyte macrophage colony-stimulating factor (GM-CSF) ---> involved in cell mediated branch of the immune response 2) Th 2 cells:-secrete IL-4, IL-5, IL-10, IL-13, and GM-CSF ---> involved in activation of B cells and the humoral (antibody- mediated) arm of the immune response. 3) Th 3 cells:-secrete transforming growth factor (TGF)- or IL-10 ---> believed to assist in regulating immune response 11.2.4 T-cell receptor and T-cell recognition • Interactions between T cells and APCs or target cells involve the ligation of adhesion molecules on opposing cells. • T cells with TCR :- 90-95% found in blood, thymus, lymph nodes, and spleen -----> primarily responsible for the antigen-specific immune response. • T cells with TCR :- present in high numbers in the skin and intestinal epithelium.

  9. 11.2.5 Overview of the Immune Response • requires the presentation of antigen by mature professional APCs (macrophages, dendritic cells (DCs), and activated B cells) • Activated lymphocytes differentiate into effector or memory cells. 1. Effector cells : Activated B cells produce antibodies : CTLseliminate target cells (virally infected cells or tumor cells) 2. Memory cells : Some lymphocytes develop into memory cells and survive for long periods of time on the periphery (unknown mechanism). : Rapid immune response is mounted upon subsequent exposure to the same antigen. 11.2.6 Overview of Lymphocyte activation • Antigens can be found essentially anywhere in the body, but T lymphocytes found primarily in the secondary lymphoid tissues (spleen and lymph nodes) and in the circulation.

  10. Dendritic cells (DCs) express MHC class I and II molecules important for activating T lymphocytes and for adhesion and costimulation of the immune response. Lymphocyte activation • Stimuli, such as infectious agents, induce maturation and mobilization of dendritic cells. CD40L CD40 • DCs attract T cells and B cells to the T-cell areas of the lymphoid organs, creating a microenvironment where lymphocyte activation and an immune response can be generated. • Cross presentation : DCs endocytose infected cells, then present exogenous antigen to CTLs after DC maturation. • CD40 ligation is required for the maturation of DCs.

  11. 11.3 Tolerance and the immune system 11.3.1 T-cell development • T cells develop and mature in the thymus from immature T cells called “thymocytes”. • The fate of the developing thymocyte is determined by TCR interactions. Basic stages of thymocyte development Th CTL

  12. Positive selection : - Thymocytes that express a TCR capable of interacting weakly with self MHC molecules are chosen to differentiate and survive. - Thymocytes that are positively selected by recognizing MHC class II/peptide complex will downregulate CD8 to become CD4+ thymocytes. • Negative selection : - The elimination of thymocytes that express a TCR with high affinity for self MHC/self peptides complexes. Thymic stromal cells thymocytes Stromal cells include thymic cortical epithelial cells, thymic medullary epithelial cells, and dendritic cells.

  13. http://www.nature.com/nri/journal/v2/n5/fig_tab/nri798_F1.htmlhttp://www.nature.com/nri/journal/v2/n5/fig_tab/nri798_F1.html

  14. 11.3.2 Central Tolerance - Central tolerance is the mechanism by which newly developing T cells and B cells are rendered non-reactive to self. - It occurs while cells are still present in the primary lymphoid organs (thymus and bone-marrow), prior to export into the periphery. 1) Clonal Deletion of immature thymocyte contribute to the elimination of self-reactive thymocytes. 2) Clonal Inactivation is also a mechanism of central tolerance. T cells specific for self antigen are present but unresponsive (anergy). 11.3.3 Peripheral Tolerance - is generated after the cells reach the periphery. - Self-reactive thymocytes can escape thymic deletion as there are proteins expressed in peripheral tissues that will not be present in the thymus during thymocyte selection. • Regulatory T cells, generated from self-reactive T cells in the thymus • during T cell differentiation, exert their immune suppression in the • periphery on other self-reactive T cells.

  15. Mechanisms of peripheral tolerance

  16. 11.3.4 Factors that influence the induction of tolerance • High level of self-antigen expression ---> clonal deletion ---> Peripheral tolerance • Low level of self-antigen expression ---> Ignorance 11.3.5 Induction of tolerance versusimmunity • Two signal model of lymphocyte activation, Bretscher and Cohn (1970). - Recognition of one antigenic determinant leads to “paralysis”. - Recognition of two antigenic determinants leads to “induction”. 11.4 Tumor Immunology 11.4.1 Innate Anti-tumor Response • The cells responsible for innate immunity include the granulocytes (neutrophils, eosinophils, and basophils),mast cells, natural killer (NK) cells, a subset of T cells called NKT cells, dendritic cell, and macrophages. • During the initiation of an immune response, dendritic cells promote NK cell activation, whereas NK cells influence dendritic cell maturation. ---> may be important in generating an immune response against tumor growth.

  17. A reduction in certain MHC class I molecules leads to NK cell-mediated destruction. • Tumor cells that have downregulated their surface MHC class I molecules are targets for NK cell lysis. • The mechanism of NK cell cytotoxicity is similar to that of CTLs. • NKT cells regulate both CTL and NK cell anti-tumor activity through cytokine secretion. • Evidence suggests that tumors express ligands for stimulatory receptors on NK and NKT cells that trigger anti-tumor activity. • NKT cells have been shown to have a role in anti-tumor immunity and therefore tumor regression, but these cells can also suppress an anti-tumor response. 11.4.2 Immunosurveillance • The cytokine INF acts as a tumor surveillance system. There is enhanced tumor development in the absence of INF. • NK and NKT cells have been shown to be involved in tumor rejection.

  18. 11.4.3 Tumor Antigens • Tumor antigen is a substance produced in tumorcells that triggers an immune response in the host. • Tumor-Specific Antigens are present only on tumor cells. • Tumor-Associated Antigens are present on some tumor cells and also some normal cells • Tumor-associated antigens may be encoded by mutant cellular genes. • Certain tumor antigens are used as tumor markers. • Tumor antigens can be used in cancer therapy as tumor antigen vaccines.

  19. Tumor antigens can be classified as; • Products of Mutated Oncogenes and Tumor Suppressor Genes • Products of Other Mutated Genes • Overexpressed or Aberrantly Expressed Cellular Proteins • Tumor Antigens Produced by Oncogenic Viruses • Oncofetal Antigens • Altered Cell Surface Glycolipids and Glycoproteins • Cell Type-Specific Differentiation Antigens 11.5 Induction of Tumor Immunity • Cancer Immunotherapy is the use of the immune system to reject cancer. • Cross presentation of exogenous tumor antigen by bone marrow-derived cells is necessary for presentation of MHC class I restricted tumor antigens and activation of CTLs against tumor antigens. • The ineffective anti-tumor responses may be due to; 1) limited cross presentation of tumor antigen 2) limited activation of sufficient numbers of CTLs in the lymph nodes.

  20. 11.5.1 Boosting the immune system • Boosting the immune system involves modulating costimulation and dendritic cells. 1) CD40 ligation on dendritic cells is required for the development of an anti-tumor immune response.

  21. 2) Modulating costimulatory signals on T cells has the potential to stimulate anti-tumor immunity. ----> Costimulatory signal = CD28 on T cell ----> B7 = ligand of CD28

  22. 11.5.2 Evasion of Immunity by tumors 1) Tumor cells downregulate the expression of MHC class I molecules. 2) Some antigenic epitopes are lost as the tumor progresses. 3) Tumors may also secrete immunosuppressive cytokines such as TGF- and IL-10, which can decrease cell-mediated immune response. 4) CD4+CD25+ regulatory T cells appear to suppress the activation of CD4+ T cells and CD8+ T cells. 11.5.3 Vaccination with Dendritic cells • Inoculation with dendritic cells exposed to tumor antigens can lead to tumor-specific protection in naïve animals in different experimental systems. ----> induction of effective anti-tumor CTL responses.

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