Tumours and immune response PDF

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Tumours: Immune response,Markers & ImmunotherapiesHallmarks of cancerThere are 6 hallmarks of cancer:  Resisting cell death  Sustaining proliferative signalling  Evading growth suppressors  Inducing angiogenesis  Enabling replicative immortality  Activating invasion and metastasis Unde...

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Tumours: Immune response, Markers & Immunotherapies Hallmarks of cancer There are 6 hallmarks of cancer:  Resisting cell death  Sustaining proliferative signalling  Evading growth suppressors  Inducing angiogenesis  Enabling replicative immortality  Activating invasion and metastasis Underlying these hallmarks are genome instability, which generates the genetic diversity that expedites their acquisition, and inflammation, which fosters multiple hallmark functions. Two enabling characteristics.  Genomic instability in cancer cells, which generates random mutations including chromosomal rearrangements; among these are the rare genetic changes that can orchestrate hallmark capabilities.  Inflammatory state of premalignant and frankly malignant lesions that is driven by cells of the immune system, some of which serve to promote tumour progression through various means. Two emerging hallmarks:  reprogramming of cellular energy metabolism in order to support continuous cell growth and proliferation  active evasion by cancer cells from attack and elimination by immune cells

What is a tumour Tumours are swelling that occurs as a consequence of these abnormal clonal growths caused by somatic mutations and is now used interchangeably with ‘neoplasm’, meaning new or abnormal cell growth. They over time evolve to

have a number of changes such as: six hallmarks, 2 emerging hallmarks and 2 enabling characteristics

Viruses and cancer Viruses are responsible for 20% of cancers. Epstein-Barr Virus (EBV) and Human Papilloma Virus (HPV) are common oncogenic viruses. EBV is associated with nasopharyngeal carcinoma and HPV strains are the major causes of cervical cancer and other ano-genital neoplasms as well as a significant proportion of head and neck tumours. Other viruses that are oncogenic:  Although many viruses can cause various tumours in animals, only seven of them are associated with human cancers and are currently considered oncogenic viruses. These viruses include hepatitis B virus (HBV), hepatitis C virus (HCV), human papillomavirus (HPV), Epstein Barr virus (EBV), human herpes virus 8 (HHV8), Merkel cell polyomavirus (MCPyV), and HTLV-1.

Immune Surveillance: What are the three primary roles of immune system? Immune system surveillance is there to help the immune system to identify cancerous/precancerous cells and eliminates them. It is the constant monitoring of normal tissues by NK cells sensitive to abnormal antigens on the surfaces of cells. It has 3 roles:  Protection from virus-induced tumours  Elimination of pathogens and resolution of inflammation  Identification and elimination of tumour cell

Immune response to tumour cells Tumours stimulate specific adaptive immune responses that can prevent or limit the growth and spread of the cancers. Immune responses involves T cells, and especially CD8+ cytotoxic T lymphocytes (CTLs). Many tumours are surrounded by mononuclear cell infiltrates composed of T lymphocytes and macrophages, and activated lymphocytes and macrophages are present in lymph node draining the sites of tumour growth. In these there are higher numbers of T cells, in particular CD8+ CTLs and CD4+ Th1 cells. CD8+ cytotoxic T-cells Tumour cells or their antigens are ingested by host APCs, particularly dendritic cells, and tumour antigens are processed inside the APCs. Peptides derived from these antigens are then displayed bound to class I MHC molecules for recognition by CD8+ T cells. The APCs carry the tumour antigens to lymph nodes and colocalise with naive T cells. The APCs express costimulators, and these or helper T cells that are activated at the same time provide the signals needed for differentiation of naïve CD8+ T cells into tumourspecific CTLs. Once effector CTLs are generated, they are able to recognize and kill the tumour cells in any tissue, without a requirement for costimulation. CD4+ T-helper cells - The antitumor effects of Th1 cells reflect their role in enhancing CD8+ T cell responses and activating macrophages, through the secretion of tumour necrosis factor (TNF) and interferon-γ (IFN-γ). IFN-γ can increase tumour cell class I MHC expression and sensitivity to lysis by CTLs.

There is some evidence that suggests that human CD4+ T cells that express granzyme B and have cytotoxic activity may contribute to tumour killing.

Immunoediting Immune system not only protects the host against tumour formation, but also shapes tumour immunogenicity. Immune selection pressure favours the development of less immunogenic tumours, which escape recognition by a functioning immune system. Cancer immunoediting is a dynamic process composed of three distinct phases: elimination, equilibrium and escape. Elimination The elimination phase is a contemporary view of the original immunosurveillance hypothesis, in which the innate and adaptive immune systems work together to successfully remove developing tumours. For the innate immune response, several effector cells such as natural killer cells and T cells are activated by the inflammatory cytokines, which are released by the growing tumour cells, macrophages and stromal cells surrounding the tumour cells. The recruited tumour-infiltrating NK cells and macrophages produce interleukin 12 and interferon gamma, which kill tumour cells by cytotoxic mechanisms such as perforin, TNF-related apoptosis-inducing ligands (TRAILs), and reactive oxygen species.[3][1] Most of the tumour cells are destroyed in this phase, but some of them survive and are able to reach equilibrium with the immune system. The elimination phase can be complete, when all tumour cells are cleared, or incomplete, when only a portion of tumour cells are eliminated. The elimination phase consists of the following four phases:  The first phase is initiation of an antitumor immune response. Cells of the innate immune system recognize the presence of a growing tumour which has undergone stromal remodelling, causing local tissue damage. This is followed by the induction of inflammatory signals which is essential for recruiting cells of the innate immune system to the tumour site. During this phase, the infiltrating lymphocytes such as the natural killer cells and natural killer T cells are stimulated to produce IFN-gamma.  In the second phase, newly synthesized IFN-gamma induces tumour death as well as promoting the production of chemokines CXCL10, CXCL9 and CXCL11. These chemokines play an important role in promoting tumour death by blocking the formation of new blood vessels. Tumour cell debris is ingested by dendritic cells, followed by the migration of these dendritic cells to the draining lymph nodes. The recruitment of more immune cells also occurs and is mediated by the chemokines produced during the inflammatory process.  In the third phase, natural killer cells and macrophages transactivate one another via the mutual production of IFN-gamma and IL-12. This promotes tumour killing by these cells via apoptosis and the production of reactive oxygen and nitrogen intermediates. In the draining lymph nodes, tumour-specific dendritic cells trigger the differentiation of Th1 cells which in turn facilitates the development of cytotoxic CD8+ T cells also known as killer T-cells.  In the final phase, tumour-specific CD4+ and CD8+ T cells which are the home to the tumour site and the cytotoxic T lymphocytes destroy the antigen-bearing tumour cells which remain at the site.

Equilibrium Tumour cells that have escaped the elimination phase and have a nonimmunogenic phenotype are selected for growth. Lymphocytes and IFN-gamma exert a selection pressure on tumour cells which are genetically unstable and rapidly mutating. Tumour cell variants which have acquired resistance to elimination then enter the escape phase. It is the longest of the three processes in cancer immunoediting and may occur over a period of many years. Thanks to mutations new tumour cell variants appear with various mutations that additionally increase the overall resistance to the immune systems attack. Escape Tumour cells continue to grow and expand in an uncontrolled manner and may eventually lead to malignancies. During the escape phase, tumour cell variants selected in the equilibrium phase have breached the host organism's immune defences, with various genetic and epigenetic changes giving further resistance to immune detection. There are many mechanisms that lead to escape of cancer cells to immune system, for example downregulation or loss of expression of classical MHC class I (HLA-A, HLA-B- HLA-C) which is essential for effective T cell-mediated immune response, development of cancer microenvironment which has suppressive effect on immune system and works as an protective barrier to cancer cells. Cells contained in tumour microenvironment are able to produce cytokines which can cause apoptosis of activated T lymphocyte. Another mechanism of tumour cells to avoid immune system is upregulation of nonclassical MHC I (HLA-E, HLA-F, HLA-G) which prevents NK-mediated immune reaction by interaction with NK cells. The tumour begins to develop and grow after escaping the immune system.

Types of tumour antigens Unique tumour antigens somatically altered and mainly point-mutated epitopes recognized by T lymphocytes from peripheral blood or tumour site of cancer patients that are “strictly” unique. They also include also the idiotypic determinants of the

rearranged immunoglobulin of B-cell malignancies. It could be specified by the HLA constraint on T-cell recognition, rather than by the presence of the altered gene only in one tumour. Viral proteins and epitopes generated by chromosomal translocations include those derived by fusion proteins, such as BCR-ABL are also included.  ABL1, is a normal gene coding for a kinase; It is a proto-oncogene, that could become an oncogene, due to mutations or increased expression.  BCR is a gene that codes for kinase, but the functions are unclear  Translocation of the proto-oncogene tyrosine-protein kinase (ABL1) gene located on chromosome 9 to the breakpoint region (BCR) gene located on chromosome 22 results in a BCR-ABL1 fusion gene on the Philadelphia chromosome. The tyrosine kinase is always on, which results in uncontrollable cell division = cancer. Cancer testis (C/T) antigens They are immunogenic, highly cancer-specific proteins expressed in gametes and trophoblasts and in many types of cancers but not in normal somatic tissues.  More than 200 cancer-testis genes in over 40 different gene families have been identified. About half are encoded by genes on the X chromosome and the rest are distributed on the other chromosomes.  It is hypothesised that in most somatic cells, the genes encoding these proteins are silenced by epigenetic mechanisms such as methylation of the promoter regions, but the loci are demethylated in cancer cells, allowing the genes to be expressed.  Normally CT antigen expression is only found in male germ cells, but ectopic expression can be seen in tumour cells of multiple types of human cancer Differentiation Antigens Differentiation antigens are found normally on tumour cells and on the cell types of origin of the tumours that have the same lineage at an earlier stage of differentiation but not on cells from other tissues.  In many cases differentiation antigens do not produce an immune response because they are normal self-antigens. Even in these situations, differentiation antigens are important in oncology because they help in accurate diagnosis of tumour types and serve as targets for passive immunotherapy.  If targeted in clinical trials it can cause autoimmunity. Overexpressed Antigens Some proteins are expressed at abnormally high levels in tumour cells because the genes encoding these proteins are amplified. Their function promotes tumourigenesis.  One example of such a protein is the oncogenic epidermal growth factor variant called Her2/Neu, which is overexpressed in some breast cancers.  A monoclonal antibody targeting Her2 is used to treat patients whose tumours show high Her2 expression. Around 15-20% of invasive breast cancers have a higher than normal level of HER2 on their cell surface. HER2 stimulates them to grow and spread.  All invasive breast cancers are tested for HER2 levels.

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IHC (immunohistochemistry) and FISH (fluorescent in situ hybridisation) are used to diagnose the HER2 levels

Immune evasion Intrinsic to tumour cells  Loss of antigens - achieved through the acquisition of defects in antigen processing and presentation or through the loss of immunogenic tumour antigens.  Hidden cell surface antigens  No expression of MCH I or other co-stimulators - some cancer cells lower their MHC I expression and avoid being detected by the cytotoxic T cells. This can be done by mutation of MHC I gene, or by lowering the sensitivity to IFN-γ. They can also stop expressing molecules essential for co-stimulation of cytotoxic T cells, such as CD80 or CD86 to escape cytotoxic T cells.  Engage inhibitory molecules  Secrete factors that suppress anti-tumour immunity - An example of an immunosuppressive tumour product is TGF-β, which is secreted by many tumours and inhibits the proliferation and effector functions of lymphocytes and macrophages Extrinsic to tumours  Tumour-associated macrophages (M2 type) promote growth promotes angiogenesis, and matrix metalloproteinases, enzymes that modify the extracellular tissue  T-regulatory cells suppress T cell response to tumour - Evidence from mouse tumour studies and cancer patients indicates that the numbers of regulatory T cells (Tregs) are increased in tumour-bearing individuals, and these cells can be found in the cellular infiltrates in certain tumours.  Myeloid-derived suppressor cells (MDSCs) are immunosuppressive; They interact with T-cells, Dendritic cells and Macrophages and Natural Killer cells to regulate their function.

Cancer immune therapy Passive immunotherapy Involves the transfer of tumour-specific antibodies into patients, which is a rapid and theoretically very specific approach but does not lead to long-lived immunity  Avastin - Avastin directly binds vascular endothelial growth factor (VEGF) to inhibit angiogenesis. Early effects of inhibiting VEGF with Avastin may lead to a reduction in tumour size. Avastin, in combination with fluoropyrimidine-irinotecan- or fluoropyrimidine-oxaliplatin-based chemotherapy, is indicated for the second-line treatment of patients with metastatic colorectal cancer who have progressed on a first line Avastin-containing regimen.  Erbitux - an epidermal growth factor receptor (EGFR) inhibitor used for the treatment of metastatic colorectal cancer, metastatic non-small cell lung cancer and head and neck cancer. It is a chimeric (mouse/human) monoclonal antibody given by intravenous infusion.  Herceptin - it is a recombinant IgG1 kappa, humanized monoclonal antibody 6 that selectively binds with high affinity to the extracellular

domain of the human epidermal growth factor receptor protein (HER2). It is used as a treatment of human epidermal growth factor receptor (HER2) in breast cancer and some bowel cancers. Limitations:  Antibody therapy has a number of limitations in addition to their cost.  since a memory response is not generated, repeated antibody infusions are required.  antibodies are chimeric or humanized and retain a small murine component, they are themselves potentially immunogenic, which may cause problems with repeated administration.  antibodies can only recognize specific proteins which are present on the cell surface, which limits the range of available targets.  Cancer antigens may not be same in different patients and hence Mabs are effective only in 20-30% of cases  Mabs are not administered as first line therapy  Mabs can be toxic (e.g. autoimmune diseases)  Tumour cells mutate as a result of radiation and chemotherapy and Mab target is not available Active immunotherapy Given to people already with the disease and they boost the body’s immune system to defend against cancer. An example is Cancer vaccines.  Divided into two sub-categories, prophylactic or therapeutic. Prophylactic Cancer Vaccines are aimed to prevent cancer in patients who may be at high risk of developing cancer due to genetic predisposition or environmental factors. Therapeutic vaccines on the other hand are intended to treat an existing tumour. Types of cancer vaccines:  Cell based vaccines - Created using patient’s own cancer cells (e.g. dendritic cells). The activated cancer cells delivered back to patient with other proteins (e.g. IL-2) leading to immune activation. Proinflammatory molecules are used to enhance the numbers of activated dendritic cells at the vaccination site. These adjuvants include Toll-like receptor (TLR) ligands, such as CpG DNA and mimics of dsRNA, and cytokines such as granulocyte-macrophage colony-stimulating factor (GM-CSF) and IL-12.  Antigen vaccines - Proteins or peptides that are antigenic are produced using recombinant strategies, purified and administered. Tumour antigens are delivered in the form of dendritic cell vaccines. The dendritic cells are purified from patients, incubated with tumour antigens, and then injected back into the patients.  Vector-based vaccines - Engineered virus or other vector is used to introduce carry specific proteins to recognize cancer cells and fight against. These may be the best ways to induce cytotoxic T lymphocytes. responses because the encoded antigens are synthesized in the cytosol of cells, such as dendritic cells, and efficiently enter the class I MHC pathway of antigen presentation. Limitations: 

Disease stage too advanced: bulky tumor deposits actively suppress the immune system using mechanisms such as secretion of cytokines that inhibit immune activity.

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Escape loss variants (that target a single tumor antigen) are likely to be less effective. Some tumors progress rapidly and/or unpredictably, and they can outpace the immune system. Manufacturing challenges, expensive Cancer antigens may not be same in different patients and hence cancer vaccines are not effective in all cases...