Tumour Immunology Flashcards
What is the word for cancer derived from?
latin word for “crab” referring to the ability of hte organism to hold on and not let go
What are the causative agents of cancer?
viruses; chemical carinogens; spontaneous; UV and ionising radiation
What does the uncontrolled cell growth in cancer result from?
abnormally high expression of genes that induce cell proliferation; defective expression of genes that normally control proliferation
How is the induction of cancer by chemical carcinogens and UV/ionising radiation used experimentally?
in order to induce cancers in animal models
Give examples of DNA viruses that cause cancer?
HPV; hepB; EBV; HTLV1
What is the difference between cancer cells and normal cells?
clonal in origin; deregulated growth and lifespan; altered tissue affinity; resistance to apoptosis; change in surface phenotype and markers; tumour associated antigens
What is the evidence for immune control of tumours?
animal models showed that pre-treatment of mice with killed tumour material could protect against a subsequent challenge with viable cells of same tumours- vaccine, T cell deficient mice were not able to do this, T cells transferred from the immunised mouse could protect a naive mouse
Give example of normal testicular proteins that are expressed by melanoma and breast cancers?
MAGE-1 and MAGE-3
What is the benefit of having a cancer with lots of mutations?
increased chance of expressing neoantigens and therefore an ability to activate the immune system
What are the strategies of low immunogenicity that tumours use to escape the immune system?
downregulation or complete loss of MHC-I molecules; downregulation of molecules involved in antigen processing; overexpression of inhibitors of granzyme B and perforin pathway to prevent lysis
What moelcules involved in antigen processing are downregulated by tumours?
TAP1; LMP2; tapasin- tapasin is progressively lost in colorectal carcinoma
Give examples of cancers which downregulate MHC-I?
epithelial-cell cacners and melanomas
How does the tumour become treated as a self antigen?
some tumour cells don’t express any abnormal antigen so immune system isn’t able to identify them; others express antigenic peptide to T cells in the absence of costimulation thereby resulting in tolerisation
How do tumours induce immunosuppression?
encouragement of Treg development; IL-4;IL10 secretion to polarisae T cell responses; aberrant STAT3 actviation causes IL-6R receptor signalling to favour unrestrained grwoth; overexpression of TGFb; upregulation og PD-L1
How do tumours create priviledged sites?
avoid detection by creating a physical barrier made of secreted collagen or fibrin which prevents cells penetrating the barrier and remaining ignorant
How do tumours evade apoptosis?
abnormal regulation of Bcl2 family e.g Bcl-XL which are endogenous inhibitors of the mitochondrial death pathway
How do tumours have unending replicative ability?
upregulate growth receptors; expression of telomerase; have activating mutation in cell-cycle regulator genes; mutations in p53 preventing its role in DNA repair and cell cycle arrest
Who first noticed a relationship between immune activation and cancer regression?
Coley in the 1890s noticed a patients whose cancer regressed after severe skin infection so treated patients with some types of bacteria–Coley’s toxins
What are the tumour specific antigens the reuslt of?
point mutations or gene rearrangement or viral antigens
What are tumour associated antigens?
overexpressed antigens on tumour cells (also found no normal cells); developmental antigens which become derepessed; differentitation antigens
What are the types of immunotherapy?
passive immunotherapy using antibodies; adoptive cell therapy; active-specific immunotherapy using vaccines; non-specific e.g cytokines
what is bevacizumab?
anti-VEGF used in advanced colorectal cacner
What are the limitations of passive immunotherapy?
clearance by soluble antigens; antigenic variation of the tumour (heterogeneity); inefficient killing/penetration into the tumour mass
How is adoptive T cell therapy done?
excise tumour and culture TILs with IL-2 and test for high levels of IFNy production after stimulation and then clonally expand them and transfer them back in- melanoma; generate tumour specific TCR or CARs
What did a phase I clinical trial with both anti-CTLA4 and anti-PD1 demonstrate?
tumour regression in around 50% of advanced melanoma, most with tumour regression of 80% or more
Why is checkpoint blockade very successful in melanoma?
very immunogenic tumour
How may checkpoint blockade be improved?
induce tumour cell destruction then block- increased immunogenicity; identify potential neoantigens and create vaccine and give with adjuvant and blockade; or give with specific T cells
