Explain how the immune system of the host responds to the presence of a tumour

Learning objectives: This lecture provides an understanding of Tumor antigens Antitumor effector mechanism Immunosurveillance

Learning outcomes At the end of this lecture student will be able to  Prove the role of immunity in cancers  List tumor antigens and specify their importance  Describe the Immunosurveillance of cancer  Explain how the immune system of the host responds to the presence of a tumour  Explain the mechanisms by which tumors evade the immune system

Tumors arise from accumulated genetic mutations Carcinogenesis is a multistep process at both the phenotypic and the genetic levels resulting from the accumulation of multiple mutations

Nonlethal genetic damage lies at the heart of carcinogenesis A tumor is formed by the clonal expansion of a single precursor cell that has incurred genetic damage (i.e., tumors are monoclonal )

Types of genes that control cancer Four classes of regulatory genes 1.growth-promoting proto-oncogenes 2.growth-inhibiting tumor suppressor genes 3.genes that regulate programmed cell death (apoptosis) 4.genes involved in DNA repair principal targets of genetic damage

The immune system play a critical role in distinguishing self from nonself 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

Ehrlich proposed that immune-mediated recognition of autologous tumor cells can be capable of eliminating transformed cells

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

 regression of metastases after removal of primary tumor  infiltrations of tumors by lymphocytes and macrophages  lymphocyte proliferation in draining lymph nodes  increased cancer risk after immunosuppression and immunodeficiency Evidence for tumor immunity

Cancer immunoediting describe the effects of the immune system  in preventing tumor formation  in “sculpting” the immunogenic properties of tumors to select tumor cells that escape immune elimination

How does the immune system eliminate cancer cells? How do cancer cells escape from Immunosurveilance? How can we help to win the battle between immune system and cancers?

Many tumors do elicit an immune response due to tumor antigens Many tumors evade host immune response through several mechanisms

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 1.Products of Mutated Oncogenes and Tumor Suppressor Genes 2.Products of other Mutated Genes 3.Over expressed or Aberrantly Expressed Cellular Proteins 4.Tumor Antigens Produced by Oncogenic Viruses 5.Oncofetal antigens 6.Altered glycolipids and glycoproteins 7.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 antigenprocessing 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 Products of mutated genes products of β-catenin, RAS, p53, and CDK4 genes BCR-ABL protein Because the mutant proteins are present only in tumors, their peptides are expressed only in tumor cells

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

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

TUMOR ANTIGENS

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 – 1 st 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