Cancer Immunology Notes (PDF)

CANCER IMMUNOLOGY VETS2007 Chiara Palmieri ([email protected]) Learning objectives: 1. explain why tumour cells might trigger host immune responses 2. describe several ways in which host animals’ immune systems may limit tumour-cell growth 3. describe several ways in which tumour cells may interf...

CANCER IMMUNOLOGY VETS2007 Chiara Palmieri ([email protected]) Learning objectives: 1. explain why tumour cells might trigger host immune responses 2. describe several ways in which host animals’ immune systems may limit tumour-cell growth 3. describe several ways in which tumour cells may interfere with the development of host immune responses 4. explain the relationship between host animals and their tumours 5. describe the possible outcomes of host-tumour interactions TUMOUR ANTIGENS Tumour antigens are proteins, glycoproteins, glycolipids or carbohydrates expressed on the tumour cell surface. They can be exploited both for diagnostic and therapeutic purposes. Tumour antigens released into the bloodstream allow noninvasive detection of tumours and monitoring tumour response to treatment. In combination with sophisticated imaging techniques, antibodies against tumour-restricted antigens can be used to localise tumours and detect metastases. Some tumour antigens can serve as the target of effective anti-cancer therapies or therapeutic strategies can be used to enhance the immune response to tumour antigens. The main classes of tumour antigens are as follows: a. products of mutated genes: neoplastic transformation results from genetic alterations in proto-oncogenes and tumour suppressor genes; these mutated genes encode variant proteins that have never been seen by the immune system and are thus recognised as non-self. These cytoplasmic proteins may enter the class I MHC antigen-processing pathway and be recognised by CD8+ T cells. In addition, these proteins may enter the class II antigen-processing pathway in antigen-presenting cells that have phagocytosed dead tumour cells, and thus be recognised by CD4+ T cells also. Examples: mutates RAS proteins, mutated p53. b. overexpressed or aberrantly expressed cellular proteins: tumour antigens may also be normal cellular proteins that are abnormally expressed in tumour cells. It may be surprising that the immune system is able to respond to this normal self-antigen. The probable explanation is that those proteins are normally produced in such small amounts and in so few normal cells that are not recognised by the immune system and fails to induce tolerance. Examples: tyrosinase, an enzyme involved in melanin biosynthesis, expressed only in normal melanocytes and melanoma. Another group of tumour antigens, the cancertestis antigens, are encoded by genes that are silent in all adult tissues except germ cells in the testis. Although the protein is present in the testis, it is not expressed on the cell surface in an antigenic form, because sperm do not express MHC class I antigens. Another good example is the production of prostate-specific antigen (PSA) by prostate carcinomas in humans. PSA is a protease exclusively produced by the prostate epithelium. Increased blood levels of this protein indicate excessive prostate activity and one cause of this if the growth of a carcinoma. c. Tumour antigens produced by oncogenic viruses: the most potent of these antigens are proteins produced by latent DNA viruses. Examples include the FOCMA (Feline-oncornavirus-associated cell membrane antigen) antigens found on the neoplastic lymphoid cells of cats infected with feline leukaemia virus and Marek’s tumour-specific antigens found on Marek’s disease tumour cells in chickens. d. Oncofoetal antigens: proteins expressed at high levels on cancer cells and in normal developing foetal tissues. These antigens are usually poor immunogens and do not provoke protective immunity. However, oncofoetal proteins are sufficiently specific that they can serve as markers that aid in tumour diagnosis and clinical management. The two most characterised oncofoetal antigens are carcinoembryonic antigen (CEA) – normally found in the foetal intestine or expressed in presence of intestinal tumours and alpha-foetoprotein (AFP) produced by hepatoma cells and normally found only in the foetal liver. e. Altered cell surface glycolipids and glycoproteins: these altered molecules include gangliosides, blood group antigens and mucins. Mucins are glycoproteins containing numerous O-linked carbohydrate side chains on a core polypeptide. Tumours often have dysregulated expression of the enzymes that synthesise the carbohydrate side chains, which leads to the appearance of tumour-specific epitopes on the carbohydrate side chains or on the abnormally exposed polypeptide core. f. Cell type-specific differentiation antigens: Tumours express molecules that are normally present on the cells of origin. These antigens are called differentiation antigens because they are specific for particular lineages or differentiation stages of various cell types. Such differentiation antigens are typically normal self-antigens and therefore they do not induce immune responses in tumour-bearing hosts. Their importance is as potential targets for immunotherapy and for identifying the tissue of origin of tumours. Example: antibodies against CD20, a transmembrane protein that is expressed on the surface of all normal mature B cells, have broad cytocidal activity against mature B-cell lymphomas and leukaemias. Anti-CD20 antibodies also kill normal B cells, but because haematopoietic stem cells are spared, normal B cells reemerge following treatment. ANTITUMOUR EFFECTOR MECHANISMS The immune response to cancer proceeds through three stages. The first of these is elimination, during which the immune system is able to completely destroy tissue cells that have undergone neoplastic transformation. The second stage if equilibrium, during which immune-resistant tumour cells emerge, but the immune system continues to destroy susceptible cancer cells. Equilibrium may last for many years in individual patients. The final stage is escape, at which point the tumour cells have developed strategies to evade immune system detection and destruction. 1) Cytotoxic T lymphocytes: this is the dominant antitumour mechanisms in vivo. Several studies have shown that the number of tumour-infiltrating CD8+T cells is correlated with a better prognosis in a variety of cancers. Instead, CD4+ lymphocytes are generally considered to function as Thelper lymphocytes that enhance the function of CD8+ CTLs and antibody-producing B lymphocytes. 2) NK cells: these cells are capable of destroying tumour cells without prior sensitisation and thus may provide the first line of defence against tumour cells. After binding to a tumour cells, the NL cell release lytic granules that activate apoptosis in the target cell. 3) Macrophages: T cells, NK cells and macrophages may collaborate in antitumour reactivity, because IFN-γ, a cytokine secreted by T cells and NK cells, is a potent activator of macrophages. Activated macrophages may kill tumour by mechanisms similar to those used to kill microbes. Macrophage-mediated tumour cell killing is independent of MHC antigens, tumour-specific antigens, and the type of transformed cell being targeted, but direct contact between the macrophages and tumour cell is required. 4) B lymphocytes: many tumour antigens can incite both cell-mediated and humoral immune responses. Antibodies that recognise tumour antigens kill tumour cells by binding to the cells and activating a local complement cascade. In addition, antitumour antibodies may be bound by their constant regions to NK cells or macrophages, leaving the variable regions of the Igs available for specific recognition of tumour antigens. This allows the effector cells to recognise, attach to, and kill tumour cells by the mechanism of antibody-dependent cell-mediated cytotoxicity (ADCC). EVASION OF THE IMMUNE RESPONSE Most cancers occur in patients who do not suffer form any overt immunodeficiency. It is evident, then, that tumour cells must develop mechanisms to escape or evade the immune system in immunocompetent hosts. Strategies of evasion are:  Selective outgrowth of antigen-negative variants  Loss or reduced expression of MHC molecules: tumour cells may fail to express normal levels of MHC class I molecules, thereby escaping attack by cytotoxic T cells. Such cells, however, may trigger NK cells if the tumour cells express ligands for NK cell activating receptors.  Activation of immunoregulatory pathways: tumour cells may actively inhibit tumour immunity. For example, they may downregulate the expression of co-stimulatory factors on APCs; as a result, the antigen presenting cells fail to engage the stimulatory receptor CD28 and instead activate the inhibitory receptor CTLA-4 on effector T cells. Tumour cells may also upregulate the expression of PD-L1 and PD-L2, cell surface proteins that activate the programmed death-1 (PD-1) receptor on effector T cells  Secretion of immunosuppressive factors by cancer cells: TGF-β is secreted in large quantities by many tumours and is a potent immunosuppressant. Many tumours produced indolamine 2,3-dioxygenase (IDO), a potent immunosuppressive agent and a suppressor of NK cell function.  Antigen masking: tumour antigens on the cell surface may be hidden from the immune system if they are complexed with glycocalyx molecules, fibrin or even antibodies. TUMOUR IMMUNOTHERAPY The mainstays of tumour therapy currently rely on attempts to destroy tumour cells by chemotherapeutic inhibition of cell division or targeted cellular damage via procedures such as radiotherapy. Adjunctive therapies that might enhance the systemic cellular immune response (immunotherapy) also have a role in management. In general, immunotherapeutic strategies are aimed at (1) providing the patient with mature effector cells or antibodies that recognise and destroy tumours (passive immunotherapy) or (2) stimulating the immune response of the host against the tumour (active immunotherapy). Administration of monoclonal antibodies raised against tumour antigens or tumour-specific effector lymphocytes generated in vitro generates rapid but short-lived passive tumour immunity. Monoclonal antibodies raised against specific tumour antigens may be used by themselves or engineered to carry an array of substances (e.g. drugs, pro-drugs or toxins) directly to a tumour when injected intravenously. These antibodies have been referred to as “magic bullets” because of their selective targeting of tumour cells. Antitumour lymphocytes are generated by removing lymphocytes form the host or tumour and expanding them in vitro by incubation with IL2; these autologous immune cells (called lymphokine-activated killer cells –LAK cells) are then readministered to the patient. LAK cells have been induced in both cat and dog. Many approaches to stimulate active immunity of patients against tumour cells have been attempted, including vaccination with tumour cells or tumour antigens to generate antitumour CTLs, administration of cytokines to increase effector cell number and function, and nonspecific stimulation of the immune system by treatment with proinflammatory substances, such as bacterial products. Regarding the last approach, the most widely used immune stimulant is the attenuated strain of Mycobacterium bovis, BCG. This organism activates macrophages and stimulates cytokine release, thus promoting T cell activity; it may be given systematically or injected directly into the tumour mass. There are numerous examples of immunotherapy. A novel product (Oncept Il-2) has just been released for the adjunct treatment of feline injection site sarcoma. This product is a canarypox virus vector carrying the feline IL-2 gene, which is injected around the site of surgical excision of the tumour at the time of post-surgical radiotherapy. The treatment reduces the time to relapse of the tumour. The first “cancer vaccine” used therapeutically for the treatment of canine malignant melanoma has been introduced recently. This is a “naked DNA” vaccine comprising a bacterial plasmid into which is inserted the gene encoding the molecule tyrosinase, a tumour antigen expressed by melanoma cells. The vaccine contains the human tyrosinase gene, as the human molecule is sufficiently different to canine tyrosinase to engender an immune response, but also sufficiently homologous to canine tyrosinase for that immune response to target the canine molecule. When injected into a dog with oral malignant melanoma, the gene transfects dendritic cells and tyrosinase peptides are presented. This tumour antigen presentation amplifies the antitumour immune response.