Cancer Biology Chapter 3 – Flashcards
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Cancer
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- is uncontrolled proliferation and spread of clones of malignantly transformed cells - Macfarlane Burnet in the 1950s proposed the concept of immune surveillance - We have a better understanding of immune surveillance by studying tumors in immuno-compromised experimental animals & humans - Both innate and adaptive immune systems do react against many tumors
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Tumors & immune cells
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- Histopathologic studies show that many tumors are surrounded by immune cell infiltrates - The presence of lymphocytic infiltrates in some types of melanoma and carcinomas of the colon and breast cancer is predictive of a better prognosis.
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Immune responses frequently fail to prevent the growth of tumors
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- Most tumors tend to be weakly immunogenic - Immune surveillance and tumor immunity varies with the type of tumor - The rapid growth and spread of tumors may overwhelm the capacity of the immune system to effectively control a tumor - Many tumors have specialized mechanisms for evading host immune responses.
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TUMOR ANTIGENS
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- Classification of tumor antigens was based on their patterns of expression Tumor-specific antigens: antigens are unique to individual tumors They can be antigens that are shared among tumors of the same type Tumor-associated antigens: Tumor antigens that are also expressed on normal cells, whose expression is aberrant or dysregulated in tumors
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Identification of Tumor Antigens
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- The identification of many antigens expressed by naturally occurring human tumors represents a major advance in the field of tumor immunology - Various biochemical and molecular genetic approaches have been used to identify these antigens: Generation of cytotoxic T lymphocyte clone (CTL) Identification of tumor antigens recognized by tumor specific CTL's
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Generation of cytotoxic T lymphocyte clone (CTL)
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Crude method of determining specific tumor antigens You are generating clones of T cells that are specific to the tumor antigen: - Surgically remove tumors and grown them as tissue culture - T cells are isolated from peripheral blood, lymph nodes draining the tumor, or directly from tumor tissue removed from patients - Isolated T cells and tumor cells are cocultured in vitro, and individual clones can be isolated
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Identification of tumor antigens recognized by tumor specific CTL's
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You are identifying tumor antigen Based on central dogma of molecular biology i.e. every protein expressed on is translated from mRNA: - Expression libraries of cDNA derived from patient's tumor RNA are transfected into cell line - Assays are performed to detect binding of the cancer patient's serum immunoglobulins to the transfected cells - Gene sequences for targeted proteins are obtained, & encoded proteins w/ stimulated antibody responses in patient are identified
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Tumor antigens
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Many tumors express genes whose products are required for malignant transformation or for maintenance of the malignant phenotype These genes may undergo point mutations, deletions, chromosomal translocations, or viral gene insertions and produce altered peptides Peptides derived from them do not induce self-tolerance and may stimulate T cell responses in the host
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Tumor antigens can be:
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1.Products of Mutated Genes 2.Abnormally Expressed but Unmutated Cellular Proteins 3.Antigens of Oncogenic Viruses 4.Oncofetal Antigens 5.Altered Glycolipid and Glycoprotein Antigens 6.Tissue-Specific Differentiation Antigens
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Tumor antigens can be Products of Mutated Genes
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- Products of mutated oncogenes, tumor suppressor genes - Unmutated but overexpressed products of oncogenes
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Tumor antigens can be Abnormally Expressed but Unmutated Cellular Proteins
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- Tumor antigens that elicit immune responses may be normal cellular proteins that are abnormally expressed in tumor cells - Some tumor antigens are normal proteins that are produced at low levels in normal cells and overexpressed in tumor cells - One such antigen is tyrosinase, an enzyme involved in melanin biosynthesis that is expressed only in normal melanocytes and melanomas
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Abnormally Expressed but Unmutated Cellular Proteins (cont'd)
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- Cancer/testis antigens are proteins expressed in gametes and trophoblasts and in many cancer types but not in normal somatic tissues - Melanomas, including carcinomas of the bladder, breast, skin, lung, prostate and some sarcomas express this antigens - There are now more than 40 different cancer/testis antigen families identified - Function of these genes is in regulation of transcription or translation of other genes - Several X-linked cancer/testis antigens are currently being used in tumor vaccine trials
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3. Antigens of Oncogenic Viruses
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- The products of oncogenic viruses function as tumor antigens and elicit specific T cell responses - DNA virus-induced tumors are among the most immunogenic tumors known. - Epstein-Barr virus (EBV), which is associated with B cell lymphomas and nasopharyngeal carcinoma - Human papillomavirus (HPV), which is associated with cervical carcinoma - Papovaviruses, including polyomavirus and simian virus 40 (SV40), and adenoviruses induce malignant tumors in neonatal or immunodeficient adult rodents
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Antigens of Oncogenic Viruses (cont'd)
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- A vaccine against HPV is now in use - Has potential to reduce the incidence of cervical cancer in women - The vaccine is composed of recombinant HPV capsid proteins from the most common oncogenic strains of HPV - HPV-6, 11, 16, and 18 - HPV-16 and HPV-18 account for about 70% of all cervical cancers. - HPV-6 and -11 cause about 90% of genital warts - Vaccination against hepatitis B virus is also reducing the incidence of liver cancer.
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4. Oncofetal Antigens
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- Oncofetal antigens are proteins that are expressed at high levels in cancer cells and in normal developing fetal but not adult tissues - The two most thoroughly characterized oncofetal antigens are carcinoembryonic antigen (CEA) and α-fetoprotein (AFP). - CEA (CD66) is a highly glycosylated membrane protein - Expression of CD66 is increased in many carcinomas of the colon, pancreas, stomach, and breast, and serum levels are increased in these patients - The level of serum CEA is used to monitor the persistence or recurrence of the tumors after treatment
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4. Oncofetal Antigens (cont'd)
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- AFP is a circulating glycoprotein normally synthesized and secreted in fetal life by the yolk sac and liver - In adult life, protein is replaced by albumin, and only low levels are present in serum - An elevated serum AFP level is a useful indicator of advanced liver or germ cell tumors or of recurrence of these tumors after treatment
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5. Altered Glycolipid and Glycoprotein Antigens
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- They are present at higher levels on cancer cells than on normal cell - Gangliosides, including GM2, GD2, and GD3, are glycolipids expressed at high levels in neuroblastomas, melanomas, and many sarcomas - They are an attractive target for tumor-specific therapies such as antibody therapy - Clinical trials of anti-ganglioside antibodies and immunization with ganglioside vaccines are under way in patients with melanoma - Several mucins have been the focus of diagnostic and therapeutic studies, including CA-125 and CA-19-9, expressed on ovarian carcinomas, and MUC-1, expressed on breast carcinomas
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6. Tissue-Specific Differentiation Antigens
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- Tumors may express molecules that are present only on the normal cells of origin and not on cells from other tissues - These antigens are called differentiation antigens because they are specific for particular lineages or differentiation stages of various cell types - Importance is as potential targets for immunotherapy and for identification of the tissue of origin of tumors - The most successful immunotherapy for non-Hodgkin's B cell lymphomas is an anti-CD20 antibody (rituximab)
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Immune Responses to Tumors
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- Both Innate and Adaptive immune responses are seen in tumors - Innate immune cells responding to tumors includes NK cells and macrophages - Involved in killing cultured tumor cells.
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Natural Killer (NK) cell response to tumors
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NK cells detect and kill cancer cells when: - Tumor cells fail to express class 1 MHC molecules (class 1 MHC molecules are expressed on all normal healthy cells) - When a normal cell infected by viruses expresses viral antigens on cell surface using class 1 MHC - Tumor cells express NK cell activating ligands such as MIC-A, MIC-B, and ULB which are recognized by NKG2D receptor on NK cells - Tumor cells coated with antibodies specific against expressed tumor antigens
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Types of interactions between NK cells & tumor cells
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1. NK CELL NOT ACTIVATED - NO CELL KILLING 2. NK CELL ACTIVATED - KILLING OF INFECTED CELL 3. NK CELL ACTIVATED - KILLING OF STRESSED CELL
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Macrophages
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- Can inhibit and promote the growth & spread of cancers, depending on activation states - Two types of macrophages M1 and M2 - M1 has anti-tumor function and kills many tumor cells: Mechanisms include the release of lysosomal enzymes, reactive oxygen species, & nitric oxide Can also produce cytokine tumor necrosis factor (TNF), an agent that can kill tumors - M2 macrophages may contribute to tumor progression: These cells secrete vascular endothelial growth factor (VEGF), transforming growth factor-β (TGF-β), and other soluble factors that promote tumor angiogenesis
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Adaptive Immune Responses to Tumors
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- Tumors elicit both T cell-mediated (T helper, cytotoxic cell response) and humoral immune responses (antibody responses). - T cells are the principal mediators of anti-tumor immunity
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CD8 T lymphocyte / Cytotoxic T lymphocyte (CTL)
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CD8+ CTLs can directly recognize and kill tumors cells CTLs look for malignant cells that express peptides that are derived from tumor antigens and are presented on class I MHC molecules Sometime they may require cross-presentation of the tumor antigens by dendritic cells
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Induction of T cell responses to tumors by cross-priming (cross-presentation)
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• Tumor cells or their antigens are ingested by host APC (antigen presenting cells), dendritic cells • Tumor antigens are processed inside APCs • Peptides derived from these antigens are then displayed bound to class I MHC molecules for recognition by CD8+ T cells • The APCs express costimulators that provide the signals needed for differentiation of CD8+ T cells into anti-tumor CTLs • The APCs express class II MHC molecules that may present internalized tumor antigens and activate CD4+ helper T cells • Once effector CTLs are generated, they are able to recognize and kill the tumor cells without a requirement for costimulation
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CD4 helper T lymphocyte
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- CD4+ cells may play a role in anti-tumor immune responses - They provide cytokines for effective CD8 cell development - They secrete cytokines, such as TNF (tumor necrosis factor) and IFN-γ (interferon-gamma) - IFN-γ increases tumor cell expression of class I MHC molecules - IFN-γ may also activate macrophages to kill tumor cells - They can increase the sensitivity of tumor cells to lysis by CD8 lymphocytes
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Antibodies (Humoral Immunity)
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- Tumor-bearing hosts may produce antibodies against various tumor antigens - For example, patients with EBV-associated lymphomas have serum antibodies against EBV-encoded antigens expressed on the surface of the lymphoma cells - Antibodies may kill tumor cells by activating complement or by antibody-dependent cell-mediated cytotoxicity - In which Fc receptor-bearing macrophages or NK cells mediate the killing
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EVASION OF IMMUNE RESPONSES BY TUMORS
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Many cancers develop mechanisms that allow them to evade anti-tumor immune responses These mechanisms can broadly be divided into Those that are intrinsic to the tumor cells Those that are mediated by other cells
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Immune evasion by tumors - Intrinsic factors
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- Tumors may lose expression of antigens that elicit immune responses: Antigen loss variants - mutations or deletions in genes encoding tumor antigens are common - Tumor antigens may be inaccessible to the immune system: Antigen masking - The cell surface antigens of tumors may be hidden from the immune system by glycocalyx molecules, such as sialic acid-containing mucopolysaccharides
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Immune invasion by tumors types
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1. Failure to produce tumor antigen (Antigen-loss variant of tumor cell) => lack of T cell recognition of tumor 2. Mutations in MHC gene or genes needed for antigen processing (class I MHC-deficient tumor cell) =>lack of T cell recognition of tumor 3. Production of immunosupressive proteins (immunosupressive cytokines) => inhibition of T cell activation
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Immune evasion by tumors (cont'd)
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- Tumors may fail to induce strong effector T cell responses because most tumor cells do not express costimulators or class II MHC molecules: Tumor cells inhibit cross-priming / cross-presentation of tumor antigens by antigen presenting cell (APC) to CD4 cells & CD8 cells
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Immune evasion by tumors (cont'd)
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- Tumors may engage molecules that inhibit immune responses: Tumor cells trigger inhibitory pathways in T cells such as CTLA-4 or PD-1 which inhibit their activation - Secreted products of tumor cells may suppress anti-tumor immune responses: immunosuppressive tumors produce a large amounts of TGF-β (transforming growth factor-beta) which inhibits the proliferation and effector funcs. of lymphocytes & macrophages
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Extrinsic Cellular Suppression of Anti-Tumor Immunity
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M2 macrophages suppress T cell responses activation and effector functions by secreting IL-10, prostaglandin E2, and arginase and factors that promote angiogenesis, such as TGF-β and VEGF that impair Increasing the numbers of regulatory T cells in tumors which result in suppression of T cell activation and effector functions
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Extrinsic Cellular Suppression of Anti-Tumor Immunity
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- Increased recruitment of Myeloid-derived suppressor cells (MDSCs) into tumors: MDSCs are a heterogeneous group of cell types, including precursors of dendritic cells, monocytes, and neutrophils MDSCs suppress innate immune responses by secreting IL-10, which inhibits various macrophage inflammatory functions MDSCs suppress T cell responses by a variety of mechanisms: -They express arginase and inducible nitric oxide synthase, which work together in generating reactive oxygen species, such as peroxynitrite, that inhibit T cell activation -They also produce indolamine 2,3-dioxygenase, which catabolizes tryptophan needed for T cell proliferation.
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Tumor vaccines
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- Autologous dendritic cells are prepared from patients' own peripheral blood cells. - The dendritic cells are either pulsed with recombinant protein or transfected with a gene construct that expresses the protein. - leads to activation of tumor-specific T cells
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Enhancement of tumor cell immunogenicity by transfection of costimulator and cytokine genes
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- Tumor cells that do not adequately stimulate T cells on transplantation into an animal will not be rejected and will therefore grow into tumors. - Vaccination with tumor cells transfected with genes encoding costimulators or cytokines, such as IL-2, can lead to enhanced activation of T cells.
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Adoptive cellular therapy.
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- In a commonly used approach for adoptive cellular therapy, lymphocytes isolated from the blood or tumor infiltrate of a patient are expanded by culture in IL-2 and are infused back into the patient. - This treatment, often combined with systemic IL-2 administration, leads to tumor regression in some patients.
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THE ROLE OF THE IMMUNE SYSTEM IN PROMOTING TUMOR GROWTH
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- Immune system may also contribute to the development of some solid tumors - Chronic inflammation is a risk factor for development of tumors in many different tissues, especially those affected by chronic inflammatory diseases such as Barrett's esophagus, Crohn's disease, pancreatitis, and prostatitis - Chronic inflammatory states that are induced by the infectious organisms: These include gastric cancer in the setting of chronic Helicobacter pylori infection and hepatocellular carcinomas associated with chronic hepatitis B and C virus infections.
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THE ROLE OF THE IMMUNE SYSTEM IN PROMOTING TUMOR GROWTH
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Cells of the innate immune system are considered the most direct tumor-promoting culprits among immune cells are macrophages of the M2 phenotype Innate immune cells may also contribute to malignant transformation of cells by generating free radicals that cause DNA damage & lead to mutations in tumor suppressor genes & oncogenes B lymphocytes may contribute to tumor progression by their secretion of factors that directly regulate proliferation programs in tumor cells as well as by their ability to chronically activate innate immune cells present in early tumors.
