By: Sara Ibrahim Tel. # Cancer and The Immune System

Cancer and The Immune Response n Introduction n Ags expressed by cancer cells n Nature of immune response n How cancer evades immune system

Cancer Introduction n Uncontrolled growth produces a tumor or neoplasm. n A tumor that grows indefinitely and often spreads (metastasis) is called malignant-- also called cancer. n A tumor that is not capable of indefinite growth----benign.

Cell Growth Control of cell growth Growth-promoting Proto-oncogenes Growth-restricting Tumor-suppressor genes

Molecular Basis of Cancer Uncontrolled cell growth Proto-oncogenes Tumor-suppressor genes Mutations Radiation Chemicals Virus

Types of Cancer based on the tissue affected n Carcinoma: Cancer of endo or ectoderm e.g. Skin or epithelial lining of organs n Sarcomas: Cancer of mesoderm e.g. bone n Leukemias and Lymphomas: Cancers of hematopoietic cells

Types of cancers based on etiologic agent n Chemically-induced tumors u Each tumor induced by a carcinogen (benzopyrene) injected at various sites expresses a unique Ag. u Thus difficult to develop vaccine. n Virus-induced tumors u Tumors induced by same virus express same tumor Ag. u Induce a strong immune response. e.g. Gardasil – Human Papilloma Virus (HPV) induced cervical cancer n UV-induced tumors u UV radiation--->melanomas

Evidence for the role of immune system in tumor rejection n Spontaneous regression n Regression of metastases after removal of primary tumor n Infiltration of tumors by lymphocytes and macrophages n Lymphocyte proliferation in draining lymph nodes n Higher incidence of cancer after immunosuppression/immunodeficiency (AIDS, neonates, aged, transplant patients)

n The immune response to foreign antigens consists of humoral (eg, antibodies) and cellular mechanisms. Most humoral responses cannot prevent tumor growth. However, effector cells, such as T cells, macrophages, and natural killer cells, have relatively effective tumoricidal abilities. Effector cell activity is induced by cells that present tumor-specific antigens (TSAs) or tumor-associated antigens (TAAs) on their surface (these cells are called antigen-presenting cells) and is supported by cytokines (eg, interleukins, interferons. Despite the activity of effector cells, host immunoreactivity may fail to control tumor occurrence and growth.

Antigens expressed on tumor cells Major Histocompatability Complex antigens TSTA TATA TSTA: unique to a tumor Play an important role in tumor rejection. TATA: shared by normal and tumor cells Tumor-associated developmental Ag (TADA) Tumor-associated viral Ag (TAVA) Tumor-specific transplantation Ag Tumor-associated transplantation Ag

Tumor-Associated Developmental Ags n Found on cancer cells and on fetal cells. n Do not trigger anti-tumor immunity. n Used in diagnosis. u Alpha-fetoprotein(AFP) Cancers of liver u Carcinoembryonic Ag (CEA) colorectal cancer

Other Tumor associated antigens n Differentiation Ags: B cells produce surface Ig. B cell tumors have sIg Melanomas and melanocytes express MART-1 n Overexpression of Ag on tumors compared to normal cells e.g. In breast cancer, HER2/neu n Ags expressed on male germ cells and melanoma e.g. MAGE-1

Cellular Immunity n The T cell is the primary cell responsible for direct recognition and killing of tumor cells. T cells carry out immunologic surveillance, then proliferate and destroy newly transformed tumor cells after recognizing TAAs. The T-cell response to tumors is modulated by other cells of the immune system; some cells require the presence of humoral antibodies directed against the tumor cells (antibody-dependent cellular cytotoxicity) to initiate the interactions that lead to the death of tumor cells. In contrast, suppressor T cells inhibit the immune response against tumors.

n Cytotoxic T lymphocytes (CTLs) recognize antigens on target cells and lyse these cells. These antigens may be cell surface proteins or may be intracellular proteins (eg, TAAs) that are expressed on the surface in combination with class I major histocompatibility complex (MHC) molecules. Tumor-specific CTLs have been found with neuroblastomas; malignant melanomas; sarcomas; and carcinomas of the colon, breast, cervix, endometrium, ovary, testis, nasopharynx, and kidney.

n Natural killer (NK) cells are another population of effector cells with tumoricidal activity. In contrast to CTLs, NK cells lack the receptor for antigen detection but can still recognize normal cells infected with viruses or tumor cells. Their tumoricidal activity is termed “natural” because it is not induced by a specific antigen. The mechanism by which NK cells discriminate between normal and abnormal cells is under study. Evidence suggests that class I MHC molecules on the surface of normal cells inhibit NK cells and prevent lysis. Thus, the decreased level of class I molecule expression characteristic of many tumor cells may allow activation of NK cells and subsequent tumor lysis.

n Macrophages can kill specific tumor cells when activated by a combination of factors, including lymphokines (soluble factors produced by T cells) and interferon. They are less effective than T-cell–mediated cytotoxic mechanisms. Under certain circumstances, macrophages may present TAAs to T cells and stimulate tumor- specific immune response.

n Dendritic cells are dedicated antigen- presenting cells present in barrier tissues (eg, skin, lymph nodes). They play a central role in initiation of tumor-specific immune response. These cells take up tumor- associated proteins, process them, and present TAAs to T cells to stimulate the CTL response against tumor. The presence of dendritic cells in tumor tissues correlates with improved prognosis.

n Lymphokines produced by immune cells stimulate growth or induce activities of other immune cells. Such lymphokines include IL-2, also known as T-cell growth factor, and the interferons. IL-12 is produced by dendritic cells and specifically induces CTLs, thereby enhancing antitumor immune responses.

n Regulatory T cells are normally present in the body and help prevent autoimmune reactions. They are produced during the active phase of immune responses to pathogens and limit the strong immune response that could damage the host. Accumulation of these cells in cancers inhibits antitumor immune responses.

Humoral Immunity n In contrast to T-cell cytotoxic immunity, humoral antibodies do not appear to confer significant protection against tumor growth. Most antibodies cannot recognize TAAs. Regardless, humoral antibodies that react with tumor cells in vitro have been detected in the sera of patients with various tumors, including Burkitt's lymphoma; malignant melanoma; osteosarcoma; neuroblastoma; and carcinomas of the lung, breast, and GI tract.

n Cytotoxic antibodies are directed against surface antigens of tumor cells. These antibodies can exert anti-tumor effects through complement fixation or by serving as a flag for destruction of tumor cells by T cells (antibody- dependent cell-mediated cytotoxicity). Another population of humoral antibodies, called enhancing antibodies (blocking antibodies), may actually favor rather than inhibit tumor growth. The mechanisms and relative importance of such immunologic enhancement are not well understood.

Although many tumors are eliminated by the immune system (and thus are never detected), others continue to grow despite the presence of TAAs. Several mechanisms have been proposed to explain this deficient host response to the TAA

How does a tumor escape immune surveillance? n Generation of regulatory cells (CD4CD25 FoxP3 T cells) n Generation of regulatory cells (CD4 + CD25 + FoxP3 + T cells) n Secrete immunosuppressive molecules Ex: prostaglandins, transforming growth factor beta (TGF-  ), interleukin-10 (IL-10), etc. Ex: prostaglandins, transforming growth factor beta (TGF-  ), interleukin-10 (IL-10), etc. Tumor T regs MM CTL IL-10, etc

n Failure to process and present tumor Ag. tumor Macrophage T helper (Th) cell B cell Cytotoxic T lymphocyte (CTL) tumor Ag tumor MHC Class I MHC Class II

n Downregulation of MHC expression on tumor cell (CTL resistant but NK sensitive) NK cell Tumor cell

Tumors escape the action of CTL by not expressing B7 which provides 2 nd signal involved in T cell activation tumor CTL tumor Ag Class I MHC B7 CD28 n Tumors may fail to express costimulatory molecules involved in T cell activation. molecules involved in T cell activation.

Tumor escape mechanisms: Fas FasL Tumor CTL Fas FasL Tumor CTL When tumor cells express Fas Ligand, they can kill Fas + T cells, thereby escaping immune destruction.

References: n Diefenbach & Raulet, Innate and adaptive tumor immunity n Kuby, Cancer and the Immune System n Last full review/revision June 2009 by Dmitry Gabrilovich, MD, PhD,Host Response to Tumors

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