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TUMOR IMMUNOLOGY
INNATE & ADAPTIVE IMMUNITY:
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à Antigen-presenting cells (APCs) bridge the gap between innate and adaptive immunity
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The immune system detects and eliminates foreign infectious agents:
- Foreign pathogen à protective immunity
- Tumours à tumour immunity
- Innocuous substance à allergy
- Self-tissue à autoimmunity
- Foreign tissue à reproductive immunology/transplant immunology (where the
former refers to the mother’s immune system responding to the foreign fetus)
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pylori causes stomach cancer, Epstein-Barr virus causes Hodgkin’s lymphoma
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However, we must keep in mind that infectious agents only contribute to
approximately 15% of all tumours, and so we must ask the question, are there
immune responses to other tumours?
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Defective self-tolerance causes autoimmunity
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B cell recognition of foreign pathogens is mediated by antibodies – single
antibody specific for one antigen, where binding results in neutralization of
pathogenic toxins and optimization where if a pathogen is coated with
antibodies, this is a signal for it to be phagotcytosed
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The b cells produce the antibodies and go through a process where those that
produce antibodies to self are deleted – negative selection during immaturity in
the bone marrow
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T cell recognition of foreign pathogens occurs via MHC molecules, which bind to
small fragments of antigen and present them to a T cell
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This recognition is via T cell receptors – which has special features like an
antibody and specificity for short fragments of the antigen presented by selfMHC
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The role of MHC presentation is to survey the intracellular and extracellular
environment for foreign peptides, and if they are there, peptides will be
presented and bound by the MHC molecules and presented to the T cells
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T cells also undergo negative selection in the thymus to delete t cells that have a
T cell receptor that could recognise self-peptides
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MHC molecules are not selective – they can bind to any peptide they can come
into contact with – thus must undergo a selection process during maturation
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This process of negative selection means that a vast majority of B cells and T cells
produced are deleted, very few survive the selective process
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Within the innate immune response, natural killer cells play a role in tumour
surveillance
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They can recognise absence of self – theu recognize MHC class I molecules
expressed on a target cell
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If a cell expresses an MHC molecule, thus sending a negative signal and thus the
NK cell ignores the cell
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However, in viruses and tumours, the MHC molecules are lost from the target of
the cell so the peptides are not presented and avoid immune detection, but the
NK cells can recognize the absence of this MHC molecules and thus lyse the
target cell
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Exclusion of lymphocytes from certain peripheral tissues, i
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eyes, testes and
brain
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Induction of anergy in mature B and T cells
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Suppression by regulatory T cells
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William Coley first drew a link between the immune system and cancer in 1893
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He observed spontaneous remission in cancer patients following infection with a
mixture of killed infectious agents – Coley’s toxins
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Injection of irradiated tumour cells into a mouse leads to immunization via
stimulation of an immune response
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Injection of the viable cells of the tumour into the same mouse does not lead to
tumour formation – this is evidence of tumour antigen specificity in the mouse
due to protective immunity
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However, injection of the viable tumour cells from a second, independently
induced tumour into the same mouse does lead to tumour formation because
the host response permits proliferation of the cells due to a lack of protective
immunity, i
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no tumour antigen specificity has been formed
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Injection of the viable cells into an immunocompetent mouse prevents tumour
formation because the host response rejects the tumour cells
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However, an immunodeficient mouse does form a tumour because the host
response permits proliferation of the tumour cells
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Transplant patients are subjected to immunosuppressors for years in order to
prevent rejection of the new organ, however, a very common side-effect of this
immunosuppression is the development of certain types of cancer, i
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nonmelanoma skin cancer, cervical cancer and colorectal cancer
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The increased presence of TILs in the cancer is associated with a better prognosis
for that individual
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This is because tumour antigens are recognised by T cells via peptide antigens on
MHC class I on normal cells
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Tumour-specific antigens: (mostly present in melanoma’s)
- These are induced by viruses, i
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onco-viral proteins such as HPV
- Induced by mutated oncogene or tumour suppressor, i
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p53
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Induced by the formation of novel fusion products created by chromosomal
instability, i
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BCR/ABL
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Moreover, tumour cell death can be induced by chemotherapy because this
promotes T cell mediated tumour immunity – i
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dendritic cells stimulation
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IMMUNE EDITING:
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TUMOUR IMMUNE EVASION STRATEGIES:
• Hide Identity:
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The cells can produce soluble circulating tumour antigens to ‘distract’ the
immune system and keep it occupied
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For example, MUC-1 which is a transmembrane mucin that is often
overexpressed in metastatic cancers and often used as a diagnostic marker for
metastatic progression
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In carcinomas, the aberrant o-linked glycosylation of MUC1 can alter the
interaction of MUC1 with lectins of the immune system and can thereby
influence tumour-immune system interplay
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Anti-apoptotic mechanisms, i
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upregulation of BCL-2
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Lysis of B and T cells by releasing soluble FasL
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Without a stressful environment, the dendritic cells will not induce an immune
response and thus the cancer cells exploit this downregulating Myc that controls
APCs – no immune response
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Repress NKG2D ligands (MICA)
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NK2GD is a receptor on NK cells, and tumour cells that express this receptor are
more susceptible to be killed by NK and T cells
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• Tumour-induced immune suppression:
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An
increased expression of PD-L1 by tumours predicts poor outcome
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Acute inflammation is good for the body, however, persistent, chronic inflammation
can facilitate malignant transformation and promote tumour growth
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Chronic inflammation contributes to:
- Cancer initiation by generating genotoxic stress
- Cancer promotion by inducing cell proliferation
- Cancer progression by enhancing angiogenesis and tissue invasion
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pylori infection and
stomach cancer
- NSAIDs reduce the risk of developing certain cancers, i
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colon and breast cancer
- Signalling pathways involved in inflammation operate downstream of oncogenic
mutations, i
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RAS and Myc
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Inflammatory cells, chemokines and cytokines are present within tumours from
the earliest stages of tumour development
Targeting inflammatory mediators decreases the incidence and spread of cancer
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Cytokines can be both detrimental and beneficial in the immune system via tumour
surveillance and promotion:
- TNF-alpha can lead to the destruction of the cells
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Additionally, macrophages also play an important role in surveillance vs
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à Overall: the immune system plays a vital role in cancer: suppression and promotion