Lecture 13 - Tumour Immunology Flashcards
Can the immune system protect the host from cancer?
Give 3 examples of historical experiments that tried to associate the immune system with cancer?
- 1890’s: William Coley treated cancer patients with bacterial extracts to activate general systemic immunity
- 1950’s: Using rodent models, it was relatively easy to immunise against transplantable tumours and ‘tumour immunology’ was an ‘optimistic’ field. However, this was an artefact of allogenic responses (transplant rejection)
- Second of 20thC: experiments by Ludvig Gross, George Klein and more recently Theirry Boon demonstrated that a protective response can be generated against a ‘non-immunogenic murine tumour
Explain the mice model experiments that showed that tumours can be immunogenic
- inject carcingon
- tumour develops, removed
- irradiate cells and vaccination naive mouse with them
- challenge vaccinated mouse with live tumour cells and mouse remains tumour free
Explain the mice model experiments that showed that tumours can induce immunological memory
- culture tumour cells in vitro
- challenge naive mouse with live tumour cells –> tumour develops
- challenge original mouse with live tumour cells –> mouse remains tumour free
What are the three forms of evidence of tumour protective immunity in humans?
- immunosuppressed individuals more frequently develop cancer (especially virus-associated cancers) than immunocompetent individuals
- cancer patients can develop spontaneous immune response to their own tumours
- the presence of immune cells within some tumours correlates with improved prognosis e.g. colorectal cancers
What is cancer immunosurveillance?
- this concept predicts that the immune system can recognise precursors of cancer and, in most cases, destroy these precursors before they become clinically apparent
- this theory was controversial because early studies in ‘immunocompromised’ mice did not support it. (however not good models of immunocrompromisation)
- More recent work with fully immunocompromised mice indicates that the theory is correct
- however, the immune system not only protects the host for tumour development but also sculpts, or edits, the immunogenicity of tumours that may eventually form
- Therefore a new term was introduced –> cancer immunoediting
What are the 3 E’s of Cancer Immunoediting?
- Elimination - immune-mediated destruction of most cancer cells
- Equilibrium - a dynamic equilibrium between the immune system and any tumour cell variant that has survived the elimination phase. The immune response is enough to contain, but not fully extinguish these genetically unstable and mutating tumour cells
- Escape - tumour cell variants selected in the equilibrium phase now growth out in a immunologically intact environment
What are the 4 key areas of T cells for cancer therapy?
- How how might T cells detect and destroy cancer cells?
- Mechanisms by which tumours might escape the immune response
- Developing T cell-based therapies for cancer
- Potential side effects
Describe the normal interactive between APC’s and T helper cells
- T cells recognise antigens displayed on the cell surface in the form of short peptide fragments bounds to molecules of MHC
- Signal 1 = TCR interacting with MHC II
- Signal 2 = costimulatory molecole interaction e.g. CD28 on T cells interacts with CD80/CD86 on APC
What happens once a T cell has been activated by an APC?
It leaves the lymph node and enters the circulation
Moves back to the tumour site to carry out immune response
What are the 6 categories of tumour-associated antigens? Give examples
- Mutated self proteins (e.g. from DNA damage) = CDK in melanoma, beta-catenin in melanoma, Capase 8 in squamous cell carcinoma
- Aberrantly or over-expressed self protein = oncofoetal antigens, cancer-testis antigens, telomerase in many cancers
- Lineage specific (differentiation) antigens = mart1/MelanA, gp100 and tyrosinase in melanoma, surface immunoglobulin in melanoma
- Abnormal post-translocational modifications of self proteins = MUC1 over expressed in an underglycosylated form in breast and pancreatic cancer
- Viral proteins = HPV in cervial cancer, EBV in Hodgkin’s lymphoma, Nasopharyngeal carcinoma
Alternatively, target the tumour stroma? (e.g. tumour endothelial markers)
What 4 things makes a good target antigen for tumour immunotherapy?
- tumour specific –> reduce toxicity
- shared amongst patients with the same and different tumour types –> widely applicable
- Critical for tumour growth/survival –> lack of antigen-loss variants
- lack of immunological tolerance –> high avidity T cells
What are good and bad examples of tumour specific antigens?
Good - mutated self-proteins - viral antigens - cancer-testis antigens Bad - lineage specific antigens - over expressed self proteins
What are good and bad examples of antigens shared amongst tumours?
Good
- mutated self or viral proteins involved in oncogenesis
- lineage specific antigens
Bad
- mutated self proteins incidental to oncogenesis
What are good and bad examples of antigens critical for tumour growth/survival?
Good - mutated self or viral proteins - overexpressed self proteins Bad - mutated self proteins incidental to oncogenesis - lineage specifically antigens
What are good and bad examples of antigens that lead to lack of immunological tolerance?
Good - mutated self proteins - viral antigens Bad - lineage specific antigen - over-expressed self proteins
