Tumour immunology Flashcards
What did William Coley do in the 1890s?
Treated cancer patients with bacterial extracts to activate general immunity
What research was carried out in the 1950s into tumour immunology?
Using rodent models, they immunised them against transplantable tumours and this lead to the idea of tumour immunology - but in fact this was an artefact of allogenic responses
- when you transplant something from the same species into another it causes the immune system to detect non-self cells/tissues/organs and this can cause a potent allogenic response = rejection
What is the evidence of tumour protective immunity in humans?
a) immunosuppressed individuals more frequently develop cancer (esp. virus associated cancers) than immunocompetent individuals
b) cancer patients can develop spontaneous immune response to their own tumours
c) presence of immune cells within some tumours correlated with improved prognosis e.g. colorectal cancer
What are TILs?
Tumour infiltrating lymphocytes
if these lymphocytes infiltrate tumours, they appear to causes a better prognosis = strong correlation
What is cancer immunosurveillance?
Body is looking for cancer cells and when they find them they kill them- this predicts that immune system can recognise precursors of cancer and in most cases destroy them before they become critically apparent
- though this theory was controversial in immunocompromised mice
HOWEVER, later work on fully immunocompromised mice supports the theory
What does cancer immunoediting mean?
immune system not only protects the host cells from tumour development but also alters immunogenicity of tumours
What are the 3 “Es” of cancer immunoediting?
Elimination
Equilibrium
Escape
What does the elimination aspect of immunoediting entail?
immune-mediated destruction of most cancer cells
What does the equilibrium aspect of immunoediting entail?
dynamic equilibrium between immune system and any tumour cell variant that has survived elimination phase- immune system can contain the cell but can’t fully extinguish these genetically unstable and mutating cells
What does the escape aspect of immunoediting entail?
tumour cell variants selected in the equilibrium phase now grown out in an immunologically intact environment
What are the different tumour targets for the immune system (tumour associated antigens)?
Mutated self-proteins e.g. from DNA damage = CDK in melanoma, Beta-catenin in melanoma, cascade 8 in squamous cell carcinoma
Aberrantly or over-expressed self-proteins = oncofoetal antigen, cancer testis antigens, telomerase
Lineage specific antigens=Mart1/MelanA, GP100 + tyrosine in melanoma, surface immunoglobulin B
Abnormal post-translational modification of self-proteins= MUC1 over expressed in underglycoslyated breast and pancreatic cancer
Viral proteins = HPV in cervical, EBV in Hodgkins lymphoma
The alternative target is the tumour stroma- endothelial markers
What makes a good target antigen for tumour immunotherapy?
Tumour specific - reduced toxicity
Shared amongst patients with same and different tumour type= widely applicable
Critical for tumour growth/survival= lack of antigen loss variants
Lack of immunological tolerance = high avidity T cells
What are some of the mechanisms whereby tumours might escape the immune response?
- loss of HLA class 1 expression
- reduced expression of other molecules involved in antigen processing/presentation
- loss of costimulatory molecule expression (CD80, CD86)
- loss of adhesion molecules expression (ICAM1)
- loss of target antigen (melonoma)
- inhibiting T-cell infiltration = endothelium B receptors on tumour endothelium signal to prevent modulation of ICAM and therefore reduce T cell adhesion to vascular endothelium. Nitrosylation of chemokines can keep T cells from entering the tumour core
What are the mechanisms involved in immunosuppression at the tumour site?
1) transforming TGF-beta= this prevents anti-tumour T cell formation and induces Tregs
2) Indoleamine 2,3-dioxygenase (IDO) = expressed by tumours and catabolised tryptophan and can block CD8+ T cell proliferation and promote apoptosis of cd4+ T cells
3) factors inhibit differentiation, maturation and function of local dendritic cells so that dendritic cells mediate immunosuppressive effects and promote treg differentiation
What do T-reg cells do?
functionally defined by their ability to inhibit an immune response by influencing the activity of another cell type (e.g. CD4+, CD25+) and they mediate this response through cytokine release and/or cell-cell contact
TREGS= involved in immune evasion of tumours
