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Transcript
Tumor immunity Overview • Introduction • Tumor antigens • Immune response • Evasion of immune responses by malignant cells • Immunotherapy • Summary A fight between immune cells and cancer But, sometimes we lose • The idea that tumors are recognized by the immune system was first given by Paul Ehrlich Evidence for immunity to tumor • Tumors that have severe lympho-reticular infiltration have a better prognosis. • Certain tumors regress spontaneously (e.g., melanomas, neuroblastomas). • Increased incidence of malignancies (lymphoma) in immunodeficient patients. Immune reactivity to tumor • Antibodies and immune T lymphocytes (in cytotoxicity and mitogenic response assays) detected in patients with tumors. • Animals can be specifically immunized against various types of tumors. • Cancer immunoediting – Is the term used to describe the effects of immune system in preventing tumor formation and also the properties of tumor cells to escape immune recognition • Tumor immunity – Tumor Antigens: Earlier classified as tumor specific and tumor associated antigens Tumor associated antigens TAAs • In order for the immune system to react against a tumor, they must have antigens that are recognized as foreign. Tumor associated antigens TAAs • A number of alterations occur in the cell during tumorigenesis (e.g., enzymes, receptors, membrane antigens, etc.). Tumor immunity Tumor Antigens: Earlier classified as tumor specific and tumor associated antigens. Now classified according to molecular structure and source. • Products of mutated oncogenes and suppressor genes. • Products of other mutated genes as in radiation • Over-expressed self proteins • Tumor antigens produced by oncogenic viruses • Oncofetal antigens - expressed normally in fetus • Altered cell surface glycoproteins and glycolipids • Cell type differentiation antigens Tumor antigens • mutations • abnormal expression • oncogenic viruses • oncofetal antigens • altered surface modifications • tissue specific differentiation antigens Oncofetal antigens • These are proteins that are expressed at high levels on cancer cells and in normal fetal tissues, but not on adult tissues • Oncofetal antigens may appear due to derepression of preexisting genes. Two major oncofetal antigens are: Alpha-fetoprotein (AFP) Carcinoembryonic antigen (CEA) Overview • Introduction • Tumor antigens • Immune response • Evasion of immune responses • Immunotherapy • Role of immune system in promoting tumor growth • Summary Immune responses to tumors • innate immune responses • NK cells • macrophages • adaptive immune responses • T cells • antibodies Downloaded from: StudentConsult (on 4 April 2008 09:13 PM) © 2005 Elsevier • Natural killer (NK) cells They directly kill tumor cells, helped by interferon, IL-2 • Macrophages Production of antibodies by B-cells : • Tumor associated antigens stimulate production of specific antibodies by host Bcells • These specific antibodies bind to tumor cell leading to destruction of tumor through: • • a- Antibody mediated-cytotoxicity : b-Activation of complement Mechanisms by which tumours escape the immune system: • Selective overgrowth of antigen negative variants • Loss / reduced MHC expression • Lack of co-stimulation • Immunosuppressive cytokines • Antigen masking • Apoptosis of cytotoxic T cells Tumor Escape Mechanisms by which tumor escape immune defenses: 1) Reduced levels or absence of MHC molecule on tumor so that they can not be recognized by CTLs 2) Some tumors stop expressing the antigens These tumors are called “antigen negative variants” 3) Production of immunosuppressive factors by tumor e.g. transforming growth factor (TGF-β) 4) Apoptosis of cytotoxic T cells Tumor Escape 5) Tumor cells have an inherent defect in antigen processing and presentation 7) Antigens on the surface of tumors may be masked by sialic acid-containing mucopolysaccharides (glycocalyx molecules). eg: CA-125, CA19-9,CA15-5 Immunotherapy • A variety of immunopotentiating agents are used to enhance anti-tumor immunity. • They include bacterial products, synthetic chemicals and cytokines. • These exert their effects by activating macrophages and NK cells, eliciting cytokines or enhancing T-cell functions. Immunotherapy to Tumors nonspecific BCG, levamisole, cytokines. specific Killed tumor cells or their extract, Recombinant antigens, co-Stimulatory molecule genes, etc. Active Passive specific Antibodies (Monoclonal) alone or coupled to: drugs, radioisotope Summary • tumor antigens are recognized by immune system • immune response mainly mediated by CTL, NK cells and macrophages • immune evasion tumor cells • immunotherapy aims at activating the patient’s own immune system to fight the tumor