GENERAL IMMUNOLOGY PHT 324 Dr. Rasheeda Hamid Abdalla Assistant Professor E-mail rasheedahamed12@hotmail.com

TUMOR IMMUNITY

Objectives Definition of cancer, carcinogenesis ,Classification of cancer ,and Carcinogens Principal Targets of Genetic Damage Tumor Immunity Immune surveillance Tumor antigens Host Response to Tumors Host immune response evasion by tumor cells Immunodiagnosis&Immunotherapy

Definitions of Cancer and Carcinogenesis Cancer: An abnormal growth of cells which tend to proliferate in an uncontrolled way and, in some cases, to metastasize (spread). Cancer is not one disease. It is a group of more than 100 different and distinctive diseases. Cancer can involve any tissue of the body and have many different forms in each body area Cancer cells arise from host cells via neoplastic transformation or carcinogenesis.

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.

Classification of cancer Carcinomas: epithelial origin involving the skin, mucous membranes, epithlial 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.

The essence of carcinogenesis is the activation (deregulation) of genes that regulate cell growth via bypassing the host’s regulatory circuits. Multiple genes must be deregulated for the development of fully malignant tumors Physical, chemical and biological agents may cause cancer.

Principal Targets of Genetic Damage Types of genes that control cancer Four classes of regulatory genes growth-promoting proto-oncogenes growth-inhibiting tumor suppressor genes genes that regulate programmed cell death (apoptosis) genes involved in DNA repair

Cancer Cells Are Different Escape normal intercellular communication Allow for rapid growth Increased mobility of cells Invade tissues Metastasis Evade the immune system

Four mechanisms of oncogene activity to deregulate cell division

Tumor Immunity The immune system play a critical role in distinguishing self from non-self molecules Eliminating infectious agents Immune system react to antigens that it recognizes as foreign Tumor cells can be recognized by the immune system as non-self

Immune surveillance Recognition and destruction of non-self tumor cells by the immune system (immunological resistance of the host against the development of cancer)

Evidence For Tumor Immunity Regression of metastases after removal of primary tumor Infiltrations of tumors by lymphocytes and macrophages Lymphocyte proliferation in draining sites of cancer Direct demonstration of tumor-specific T cells and antibodies in patients Increased cancer risk after immunosuppression and immunodeficiency

Classification of Tumor Antigens Two Categories: based on their patterns of expression: Tumor-specific antigens - present only on tumor cells and not on any normal cells Tumor-associated antigens - present on tumor cells and also on some normal cells

Classification of Tumor Antigens based on their molecular structure and source Products of Mutated Oncogenes and Tumor Suppressor Genes Products of other Mutated Genes Over expressed or Aberrantly Expressed Cellular Proteins Tumor Antigens Produced by Oncogenic Viruses Oncofetal antigens Altered glycolipids and glycoproteins Cell type-specific differentiation antigens

TUMOR ANTIGENS Products of mutated genes derived from the products of mutant proto-oncogenes, tumor suppressor genes, or other mutated genes synthesized in the cytoplasm of tumor cells, and like any cytoplasmic protein, they may enter the class I MHC antigen processing pathway and be recognized by CD8+ T cells In addition, these proteins may enter the class II antigen-processing pathway in antigen-presenting cells that have phagocytosed dead tumor cells, and thus be recognized by CD4+ T cells also

TUMOR ANTIGENS Overexpressed or aberrantly expressed proteins Tumor antigens may be normal cellular proteins that are abnormally expressed in tumor cells and elicit immune responses Tyrosinase , MAGE(melanoma antigen gene ) is expressed on melanomas

TUMOR ANTIGENS Oncofetal antigens proteins that are expressed at high levels on cancer cells and in normal developing (fetal) but not adult tissues Their main importance is that they provide markers that aid in tumor diagnosis

TUMOR ANTIGENS Oncofetal antigens Alpha fetoprotein(AFP): Carcino-Embryonic Antigens (CEA) - Normally expressed during fetal life on fetal gut - GIT, pancreas, biliary system and cancer breast Alpha fetoprotein(AFP): - Normally expressed in fetal life - hepatocellularcarcinoma

TUMOR ANTIGENS Antigens Produced By Oncogenic Viruses Oncogenic viruses (eg; HPV,EBV, HBV) produce proteins that are recognized as foreign by the immune system

TUMOR ANTIGENS Altered Cell Surface Glycolipids and Glycoproteins Expression of higher than normal levels and/or abnormal forms of surface glycoproteins and glycolipids diagnostic markers and targets for therapy These altered molecules include gangliosides, blood group antigens, and mucins

TUMOR ANTIGENS Altered Cell Surface Glycolipids and Glycoproteins These include CA-125 - expressed on ovarian carcinomas CA-19-9- expressed on carcinoma in pancreas & biliary tract MUC-1 - expressed on breast carcinomas

TUMOR ANTIGENS Cell Type-Specific Differentiation Antigens Tumors express molecules that are normally present on the cells of origin Important for identifying the tissue of origin of tumors These antigens are called differentiation antigens because they are specific for particular lineages or differentiation stages of various cell types

TUMOR ANTIGENS Altered Cell Surface Glycolipids and Glycoproteins Mucins are high-molecular-weight glycoproteins containing numerous O-linked carbohydrate side chains on a core polypeptide Tumors often have dysregulated expression of the enzymes that synthesize these carbohydrate side chains, which leads to the appearance of tumor-specific epitopes on the carbohydrate side chains or on the abnormally exposed polypeptide core

TUMOR ANTIGENS Cell Type-Specific Differentiation Antigens typically normal self-antigens, and therefore they do not induce immune responses in tumor-bearing hosts For example, lymphomas may be diagnosed as B-cell-derived tumors by the detection of surface markers characteristic of this lineage, such as CD10 and CD20

Host Response to Tumors Cellular Immunity CTL (Cytotoxic T-lymphoctyes) NK cells Macrophages Humoral Immunity Antibody production by the host against host tumor cells or their constituents for tumor antigens

Host Response to Tumors CTL (Cytotoxic T-lymphoctyes) CTLs are the major immune defense mechanism against tumors CTLs recognize peptides derived from cytoplasmic proteins that are displayed bound to class I major histocompatibility complex (MHC) molecules CTLs play a protective role against virus-associated neoplasms (e.g., EBV- and HPV-induced tumors)

Host Response to Tumors NK cells Are capable of destroying tumor cells without prior sensitization – 1st line defense against tumor cells After activation with IL-2 and IL-15, NK cells can lyse a wide range of human tumors Recognize stress-induced antigens that are expressed on tumor cells and cells that have incurred DNA damage and are at risk for neoplastic transformation

Host Response to Tumors Macrophages Activated macrophages exhibit cytotoxicity against tumor cells in vitro Activated macrophages may kill tumors by mechanisms similar to those used to kill microbes (e.g., production of reactive oxygen metabolites or by secretion of TNF)

Host Response to Tumors T cells, NK cells, and macrophages may collaborate in antitumor reactivity interferon-γ, a cytokine secreted by T cells and NK cells, is a potent activator of macrophages

Host immune response evasion by tumor cells Selective outgrowth of antigen-negative variants loss or reduced expression of histocompatibility antigens Lack of costimulation Immunosuppression Antigen masking Apoptosis of cytotoxic T cells

Host immune response evasion by tumor cells Selective outgrowth of antigen-negative variants - during tumor progression, strongly immunogenic subclones may be eliminated loss or reduced expression of histocompatibility antigens - tumor cells may fail to express normal levels of HLA class I molecules, thereby escaping attack by cytotoxic T cells Such cells, however, may trigger NK cells

Host immune response evasion by tumor cells Lack of costimulation - sensitization of T cells requires two signals, one by a foreign peptide presented by MHC molecules and the other by costimulatory molecules - although tumor cells may express peptide antigens with class I molecules, they often do not express costimulatory molecules

Host immune response evasion by tumor cells Immunosuppression Many oncogenic agents (e.g., chemicals and ionizing radiation) suppress host immune responses Tumors or tumor products also may be immunosuppressive. For example, TGF-β, secreted in large quantities by many tumors, is a potent immunosuppressant

Host immune response evasion by tumor cells Antigen masking -The cell surface antigens of tumors may be hidden, or masked, from the immune system by glycocalyx molecules, such as sialic acid–containing mucopolysaccharides Apoptosis of cytotoxic T cells Some melanomas and hepatocellular carcinomas express FasL. It has been postulated that these tumors kill Fas-expressing T lymphocytes that come in contact with them, thus eliminating tumor-specific T cells

Immunodiagnosis Tumor antigens useful as tumor markers released only from tumor tissue Specific for a given tumor type Has direct relationship to the tumor cell Present in all patients with tumor Tumors release antigen macromolecules that can be detected in vivo and in vitro

Immunodiagnosis Examples of tumor antigens used for tumor markers Alpha-Fetoprotein Beta-subunit of human chorionic gonadotropin (B-HCG) Prostate-specific antigen (PSA) CA 125 Radio-labeled monoclonal antibody B72.3 Carcinoembryonic Antigen (CEA)

Immunodiagnosis Immunohistochemistry Categorization of undifferentiated malignant tumors Determination of site of origin of metastatic tumors Detection of molecules that have prognostic or therapeutic significance

Immunotherapy Adoptive T cell therapy (AIT) Passive immunotherapy using antibodies Active-specific immunotherapy by using vaccines

Passive immunotherapy: mAbs Herceptin: anti-HER-2/neu in breast cancer patients Rituximab: anti-CD20 in patients with non-Hodgkin’s lymphoma Limitations: clearance by soluble Ags, antigenic variation of the tumor, inefficient killing or penetration into the tumor mass