Tumour immunology COPY

Question 1

What evidence is there of the importance of tumour surveillance by the immune system?

Answer 1

1. Autopsies of accident victims have shown that many adults have microscopic colonies of cancer cells, with no symptoms of disease 2. Patients treated for melanoma, after many years apparently free of disease, have been used as sources of organs for transplantation. Transplant recipients (immunosuppressed) have developed tumours. 3. Deliberate immunosuppression (e.g. in transplantation) increases risk of malignancy 4. Men have twice as great chance of dying from malignant cancer as do women (women typically mount stronger IRs)

Question 2

How do immune responses to tumours have some similarities with those to virus infected cells?

Answer 2

MHC Class I molecules present endogenous peptides (tumour specific antigens in cancerous cells, viral peptides in virus infected cells) on their cell surface for recognition by T cells Similar mechanisms - release of cancer cell antigens, cancer antigen presentation, priming and activation of T cells by APCs, trafficking of T cells to tumours, infiltration of T cells into tumours, recognition of cancer cells by T cells, killing of cancer cells Tumours are much less inflammatory tf harder to generate lymphocyte responses

Question 3

What are tumour-associated antigens? Give examples

Answer 3

• Derive from normal cellular proteins which are aberrantly expressed (timing, location or quantity) - Because they are normal self proteins, for an IR to occur, tolerance may need to be overcome E.g. cancer-testes antigens - not expressed in normal adult tissues except male germ cells (some expressed in placenta) E.g. MAGE - melanoma associated antigens - identified in melanoma, also expressed in other tumours E.g. p53 when overexpressed

Question 4

How do tumour-associated antigens differ from tumour-specific antigens?

Answer 4

Tumour-associated antigens are self-proteins expressed by tumours that are not found in the equivalent normal cells, but may be expressed in other cells elsewhere in the body Tumour-specific antigens can be produced by tumours caused by oncogenic viruses and are recognised by the immune system E.g. p53 is tumour-associated when overexpressed and tumour-specific when mutated

Question 5

What is antibody-based therapy?

Answer 5

• Therapeutic monoclonal antibodies against tumour cells by targeting tumour-associated antigens - Can be “naked” (just antibody) or “conjugated”, e.g. radioactive particle linked to ab, drug linked to ab - “Bispecific” antibodies - genetically engineered to combine 2 specificities - Expensive

Question 6

What is immune checkpoint blockade?

Answer 6

• Reduces/removes negative regulatory controls of existing T cell responses - Targets CTLA-4 and PD-1 pathways: - CTLA-4 is expressed on activated and regulatory T cells, binds to CD80/86 (costimulatory molecules on APC) - PD-1 is expressed on activated T cells, binds to PD-L1/L2 (complex expression patterns, may be upregulated on tumours) E.g. Ipilimumab (anti CTLA-4), Nivolumab (anti PD-1), antagonistic antibodies Can be used in a wide variety of cancers