Survey
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
Monoclonal antibody wikipedia , lookup
Lymphopoiesis wikipedia , lookup
Psychoneuroimmunology wikipedia , lookup
Immune system wikipedia , lookup
Immunosuppressive drug wikipedia , lookup
Adaptive immune system wikipedia , lookup
Molecular mimicry wikipedia , lookup
Innate immune system wikipedia , lookup
Polyclonal B cell response wikipedia , lookup
Tumor immunology 20\12\2012 Dr Monem Alshok Tumor is Pathological cell masses derived by abnormal and uncontrollable clonal expansion of single cell.Transformation of normal cells to malignant cells by: a- Spontaneous mutation during daily cell division. carcinogens,chemical carcinogens & viruses b- It may be induced by : physical Cells become antigenically different from normal cells&They are recognized and destroyed by immune system. Etiology Of Tumor : 1) Inherited : Expression of inherited oncogene e.g. viral gene incorporated into host gene 2) Viral: - Human papilloma, herpes type 2, HBV, EBV (DNA) - Human T-cell leuckemia virus (RNA) 3) Chemical: - Poly cyclic hydrocarbons cause sarcomas - Aromatic amines cause mammary carcinoma - Alkyl nitroso amines cause hepatoma 4) Radiological: Ultraviolet & ionizing irradiation 5) Spontaneous: failure in the cellular growth control Malignant Transformation is the proliferation of normal cells is carefully regulated. However, such cells when exposed to chemical carcinogens, irradiation and certain viruses may undergo mutations leading to their transformation into cells that are capable of uncontrolled growth, producing a tumor or neoplasm. A tumor may be: 1) Benign, if it is not capable of indefinite growth and the host survives. 2) Malignant, if the tumor continues to grow indefinitely and spreads (metastasizes), eventually killing the host. This uncontrolled growth may be due to upregulation of oncogenes (cancer-inducing genes) and/or downregulation of tumor suppressor genes (that normally inhibit tumor growth often by inducing cell death). 1 Evidence for existence of an immune response against tumors:The following criteria serve as evidence that tumors can elicit an immune response. 1. Tumors that have severe mononuclear cell infiltration have a better prognosis than those that lack it. 2. Certain tumors regress spontaneously (e.g., melanomas, neuroblastomas).suggesting an immunological response. Some tumor metastases regress after removal of primary tumor which reduces the tumor load, thereby inducing the immune system to kill the residual tumor.. 3. Although chemotherapy leads to rejection of a large number of tumor cells, the few tumor cells that evade the action of the drugs can outgrow and kill the host. However, the immune system may be able to mount an attack against the few tumor cells that are spared by the chemotherapeutic agent. 4. There is an increased incidence of malignancies in immunodeficient patients such as AIDS patients who are susceptible to Kaposi sarcoma and transplant patients who are susceptible to Epstein Barr virus (EBV)-induced lymphoma. 5. Tumor-specific antibodies and T lymphocytes (detected in cytotoxicity and proliferative response assays) have been observed in patients with tumors. 6. The young and the old population have an increased incidence of tumors. These members of the population often have an immune system that is compromised. Lastly Hosts can be specifically immunized against various types of tumors demonstrating tumor Ags can elicit an immune response What is Oncogenes? Is a gene which, when mutated or introduced (by an oncogenic virus), facilitates neoplastic proliferation. In normal host the normal function of such genes is usually to produce factors involved in growth control, the cell cycle or apoptosis.e call it (Proto oncogen ) Oncogenes can be broadly divided into two groups, according to whether their oncogenic effect is gain of a pro-oncogenic gene (i.e. overactivity of a 'proto-oncogene' or gain of an oncogenic virus) or loss of an endogenous anti-oncogenic 'tumour suppressor' function of the proto oncogen . What is the concept of immune surveillance? Do tumour cells show differences from their normal cellular counterparts that the immune system can recognize? If so, it would be interesting to know whether TAAs are specific for the particular cancer involved or whether they represent simple differentiation into malignant cells.If tumour associated antigens do exist, does the immune response 2 directed against these antigens give rise to death of the tumour cell? During neoplastic transformation, new antigen develop&The host recognize them as nonself antigens&Cell mediated immune reactions attack these nonself tumor cells * Immune response act as surveillance system to detect and eliminate newly arising neoplastic cells. This system include : 1) Natural killer (NK) cells They kill directly tumor cells,helped by interferon, IL-2 2) Cytotoxic T-cells They also kill directly tumor cells 3) Cell mediated T-cells (effector T-cells) They produce and release a variety of lymphokines : a-Macrophage activation factor that activate macrophage b-Gamma interferon and interleukin-2 that activate NK c-TNF (cachectine) 4) B-cells :Tumor associated antigens stimulate production of specific antibodies by host Bcells .These specific antibodies bind together on tumor cell surface leading to destruction of tumor through: a- Antibody mediated-cytotoxicity : kill IgG-coated tumor cells by Cytotoxic Tcells . b- Activation of macrophages by release of Sensitized T-cells macrophage activating factor causes activation of macrophages c- IgG-coated tumor cells Activation of classical pathway of complement leading to Lysis of tumor cells Surface Antigens on Tumour Cells : Tumorigenesis may lead to expression of new antigens or alteration in existing antigens that are found on normal cells. These antigens may include membrane receptors, regulators of cell cycle and apoptosis, or molecules involved in signal transduction pathways. Tumour antigens fall into 2 broad categories: 1 .The tumour specific antigens (TSA) are unique, found only on tumour cells and are eminently positioned as targets for immunologic attack.or called Tumor-specific transplantation antigens (TSTA) which are unique to tumor cells and not expressed on normal cells. These antigens may include membrane receptors, regulators of cell cycle and apoptosis, or molecules involved in signal transduction pathways. They are responsible for rejection of the tumor. 3 2 . The tumour-associated antigens (TAA), by contrast, are found on tumour cells and some normal cells as well.Also we call it Tumor associated transplantation antigens (TATA) that are expressed by tumor cells and normal cells. Although chemical- , UV- or virus-induced tumors express neo-antigens, majority of the tumors are often weakly immunogenic or non-immunogenic. In most cases, tumor-specific transplantation Ags cannot be identified easily. Also, some of these antigens may be secreted while others include membraneassociated molecules. The majority of tumor Ags are also present on normal cells and are referred to as tumor associated transplantation antigens (TATA). They may be expressed at higher levels on tumor cells when compared to normal cells. Alternatively, they may be expressed only during development of cells and lost during adult life but re-expressed in tumors. Unique Tumour Specific Antigens are found only on tumour cells and not on other cells of the host. There are several examples of unique tumour specific antigens (TSAs) include : (a) Virally Induced Antigens :The best example of unique TSAs are those induced by viruses. In mammals, several RNA virsuses (example: retroviruses) and DNA viruses (example: herpes viruses) cause malignant transformation. The best example and the greatest triumph so far in tumour immunology is that of Marek’s disease in chickens, caused by a herpes virus. The virus infects the lymphocyte and transforms it; a unique protein is found on the membrane of the transformed lymphocyte when the viral DNA integrates with the host cell genome. All tumours due to this virus carry this surface antigen and antibodies to the protein are detectable in host sera. It is now possible to immunize animals prophylactically against Marek’s disease, using either the whole virus or the TSA. Tumour cells induced by RNA viruses express antigens coded for by the viral protein in addition to their own cell surface antigens. These may be viral envelope antigens or intra viral proteins. Antigens of virally induced tumours show extensive cross reactivity; immunization of animals with any of these viruses provides protection against a variety of similar viruses. Common oncogenic RNA viruses are the human T cell leukaemia virus (HTLV) in man and the feline leukaemia virus (FeLV) in cats. In many of these oncogenic viruses, it has been shown that viral antigens activate cellular oncogenes leading to cell transformation. Some of these oncogene products will render malignant cells sufficiently disparate from normal cells. This could also explain the extensive cross reactivity between the TSAs of oncogenic viruses. (b) Chemically or Physically Induced Tumour Antigens :Alterations in both major and minor histocompatibility antigens on tumours have been described in chemical carcinomas. The same mechanism is said to operate in tumours due to ultraviolet light or radiation. Generation of an enormous variety of distinct tumour antigens makes it unlikely that immunization against such cancers will ever be possible. 4 (c) Antigens of Spontaneous Tumours: Spontaneous tumours are those that have no known inducing agent. Though antigens differing from normal cellular antigens have been identified, it has not been possible to characterize a unique TSA from such tumours. Tumor Associated Antigens ( TATA )or (TSTA) 1) Viral Antigen : a- Viral proteins and glycoproteins b- New antigens produced by virally infected host cells under control of viral nucleic acid 2) Tumor specific antigens :Tumor cells develop new antigen specific to their carcinogens 3) Tumor specific transplantation antigens :Tumor cells express new MHC antigens due to alteration of normally present MHC antigens 4) Oncofetal antigens: Oncofoetal antigens ( AFP &CEA) Most oncogenes were actually present in the host cell, where they functioned in regulated cell growth. The host cell gene was called a proto-oncogene. When transduced by the virus and expressed under the control of a viral promotor, the gene product contributes to the unregulated growth of the tumour cell. Since proteins encoded by proto-oncogenes are expressed by normal cells, their over-expression on tumour cells would qualify them as tumour-associated antigens. Tumour cells can sometimes “switch on” genes which are associated with growth and development of the foetus. Consequently, antigens which are associated normally with embryogenesis and are not detectable in the adult begin to appear during tumour growth. The prototype oncofoetal antigen is (CEA), which is an improperly glycosylated glycoprotein found on foetal gut and human colon cancer cells, but not on normal adult colonic cells. Such abnormal glycosylation may be the cause of the observation that certain human gastric carcinoma cells display ABO blood group antigens different from the host ABO blood group.CEA is useful in monitoring response to treatment ( a ) Carcinoembryonic antigens (CEA) Normally expressed during fetal life on fetal gut but there is Reappearance in adult life in GIT, pancreas, biliary system and cancer breast (b)Alpha fetoprotein:Normally expressed in fetal life but Reappearance in adult life;in hepatoma Immune response to tumors Evidence for immunity against malignancy comes mostly from experimental studies, wherein mice were immunized by administering irradiated tumor cells or following removal of a primary tumor challenged with the same live tumor. These animals were found to be resistant to rechallenge with the same live tumor. While Abs may develop against few cancers, cell-mediated immunity plays a critical role in tumor rejection. Thus, immunity can be transferred, in most cases, from an animal, in which a tumor has regressed, to a naive syngeneic recipient by administration of T lymphocytes. The T helper 5 (Th) cells recognize the tumor Ags that may be shed from tumors and internalized, processed and presented in association with class II MHC on antigen presenting cells. These Th cells when activated will produce cytokines. Thus, the Th cells provide help to B cells in Ab production. The cytokines such as IFN-γ may also activate macrophages to be tumoricidal. Furthermore, the Th cells also provide help to tumor-specific cytotoxic T cell (CTL) by inducing their proliferation and differentiation. The CTLs recognize tumor Ags in the context of class I MHC and mediate tumor cell lysis. In tumors that exhibit decreased MHC Ags, natural killer (NK) cells are important in mediating tumor rejection . Cellular Immunity against cancers include : (a) T cells ( b )Macrophage ( c ) NK, LAK( Lymphokines activated Killer cell ) ( d ) B cells and antibody dependant cellular cytotoxicity What is the Mechanisms by which tumor escape immune defenses? 1) Reduced levels or absence of MHCI molecule on tumor so that they can not be recognized by CTLs 2) Some tumors stop expressing the antigens These tumors are called “antigen loss variants” 3) Production of immunosuppressive factors by tumor e.g. transforming growth factor (TGF-β) 4) Tumor antigens may induce specific immunologic tolerance 5) Tumor cells have an inherent defect in antigen processing and presentation 6) Blocking of receptors on T-cells by specific antigen antibodies complex (after shedding of tumor Ag) prevents them from recognizing and attacking tumor cells 7) Antigens on the surface of tumors may be masked by sialic acid-containing mucopolysaccharides 8) Immune suppression of the host as in transplant patients who show a higher incidence of malignancy Immunodiagnosis in Cancer : Tumor Associated Antigens can be useful tumour markers in the diagnosis and management of various tumours. An ideal tumour marker is released only from tumour tissue, is specific for a given tumour type (to direct diagnostic 6 assessment), is detectable at low levels of tumour cell burden, has a direct relationship to the tumour cell burden and the marker concentration in blood or other body fluid, and is present in all patients with the tumour. Most tumours release antigenic macromolecules into the circulation that can be detected by immunoassay. Although useful in monitoring patients for tumour recurrence after therapy, no tumour marker has undisputed specificity or sensitivity for application in early diagnosis or mass cancer screening programs. Tumor Markers Tumor markers :They are either Tumor antigens or Tumor products (enzymes and hormones) Tumor products are released in the serum of patients They are used to confirm diagnosis and follow up the response to therapy Examples of tumor markers : Carcinoembryonic antigen (CEA) is a protein-polysaccharide complex found in colon carcinomas and in normal foetal intestine, pancreas, and liver α-Fetoprotein, a normal product of foetal liver cells, is also found in the sera of patients with primary hepatoma, yolk sac neoplasms, and frequently, ovarian or testicular embryonalcarcinoma. β-Subunit of human chorionic gonadotropin (β-HCG), measured by immunoassay, is the major clinical marker in women with gestational trophoblastic neoplasia, about 2/3 of men with testicular embryonal or choriocarcinoma Prostate-specific antigen (PSA), a glycoprotein located in ductal epithelial cells of the prostate gland, CA 125 is clinically useful for diagnosing and monitoring therapy for ovarian cancer Tumor Products : a) Hormones : - Human chorionic gonadotrophins (HCG) are secreted in cases of choriocarcinoma - Thyroxin (T3 & T4) is secreted in cases of cancer of thyroid gland b) Enzymes : - Acid phosphatase enzymes in cases of cancer prostate 7 - Alkaline phosphatese, lipase and amylase enzymes in cases of cancer pancreas Immunotherapy Immunotherapy has been used as a novel mode to treat cancer. Both active and passive means of stimulating the non-specific and specific immune systems have been employed, in some cases with significant success . 1) Active Immunotherapy: Wherein the host actively participates in mounting an immune response include : a) Nonspecific activation is achieved by immunization with: i) Bacillus CalmetteGuerin (BCG) ii) Corynebacterium parvum These activate macrophages to be tumoricidal. b) Specific activation using vaccines: i) Hepatitis B vaccine ii) Human Papilloma virus (HPV) vaccine & iii) Defined tumour antigen-based vaccines are among the most promising approaches in cancer immunotherapy. An increasing number of tumour antigens have been unequivocally identified as the target of specific T cells grown from cancer patients. 2) Passive Immunotherapy: This involves transfer of preformed Abs, immune cells and other factors into the hosts. a) Specific : i) Antibodies against tumor Ags (e.g. Her2/Neu for treatment of breast cancer) ii) Abs against IL-2R for Human T lymphotropic virus (HTLV-1)-induced adult T cell leukemia iii) Abs against CD20 expressed on non Hodgkin’s B cell lymphoma. These Abs bind to tumor Ags on the cell surface and activate complement (C’) to mediate tumor cell lysis. In addition, Fc receptor bearing cells such as NK cells, macrophages and granulocytes may bind to the Ag-Ab complexes on tumor cell surface and mediate tumor cell killing through Ab-dependent cell-mediated cytotoxicity. iv) Abs conjugated to toxins, radioisotopes and anti-cancer drugs have also been used. These enter the cells and inhibit protein synthesis. e.g. anti-CD20 conjugated to Pseudomonas toxin or ricin toxin. There are several problems with the use of Abs 1) Abs are not efficient because the tumor Ags are associated with class I MHC Ags. 2) The tumors may shed Ag or Ag-Ab complexes. Thus, immune cells cannot mediate tumor destruction. 3) Some Abs may not be cytotoxic. 8 4) Abs may bind nonspecifically to immune cells expressing the Fc receptors which include NK cells, B cells, macrophages and granulocytes without binding to tumor cells. b) Non specific : i) Adoptive Transfer of lymphocytes: (1) Lymphokine-activated killer (LAK) cells which are IL-2 activated T and NK cells. (2) Tumor-infiltrating lymphocytes (TIL) ii) Dendritic cells pulsed with tumor Ags may induce tumor-specific T cell responses. As tumor Ags are usually not known, tumor lysates are used. iii) Cytokines ( examples ) : (1) IL-2: Activates T cells/NK cells expressing IL-2 receptors. Used in the treatment of renal cell carcinoma and melanoma, (2) IFNα: Ιnduces MHC expression on tumors and used in the treatment of hairy B cell leukemias (3) IFN-γ: Ιncreases class II MHC expression; used in the treatment of ovarian cancers. (4) TNF-α: Kills tumor cells. iv) Cytokine gene transfected tumor cells may also be used which can activate T or LAK cell-mediated anti-tumor immunity. 9 10