Tumours and Cancer Flashcards
- Tumours can express antigens that are XXXXXX corresponding normal tissues
absent from (or not detectable in)
Possible problem that can arise from immune destruction of tumour cells
In certain cases, this may result in auto-immune destruction of normal somatic tissues
4 pieces of evidence that there is immune control of tumours
- Autopsies of accident victims have shown that many adults have microscopic colonies of cancer cells, with no symptoms of disease Has the immune system suppressed tumour growth?
- Patients treated for melanoma, after many years apparently free of disease, have been used as donors of organs for transplantation Transplant recipients have developed tumours Had the original patient developed immunity?
- Deliberate immunosuppression (e.g. in transplantation) increases risk of malignancy
- Men have 2x the chance of dying from malignant cancer as do women (women typically mount stronger immune responses)
T cells have an XX T cell receptor and are Y and Z restricted, while B cells have a B cell antigen receptor which is an A, and can recognise BB
alphabeta MHC class I class II antibody many molecules
Describe how the immune system recognises and destroys a tumour, starting with the development of a tumour
- We have a tumour
- Some of the tumour cells may be dying or releasing antigens
- Those antigens can be captured by APCs such as dendritic cells
- They can migrate to local draining lymph nodes
- They’ll present antigen to T cells and activate them
- The T cells will then go via circulation back to the site of the tumour
- They can leave the circulation and infiltrate the tumour (cells that do this are called TUMOUR INFILTRATING LYMPHOCYTES (TILs))
- They can recognize the cancer cells This puts a large immune selection pressure on the cancer cells
- They can then kill cancer cells
What do we call lymphocytes that can leave the circulation and recognise cancer cells
TUMOUR INFILTRATING LYMPHOCYTES (TILs))
What is immune checkpoint blockade
blocking inhibitory molecules to enhance T cell response
2 Requirements for activation of adaptive anti-tumour immune response
- Local inflammation in the tumour
- Expression and recognition of tumour antigens
PROBLEMS IN IMMUNE SURVEILLANCE OF CANCER:(2)
- It takes the tumour a while to cause local inflammation
2. Antigenic differences between normal and tumour cells can be very subtle (e.g. small number of point mutations)
HOW DO IMMUNE RESPONSES TO TUMOURS HAVE SIMILARITIES WITH THOSE TO VIRUS INFECTED CELLS?
- Many tumour antigens are intracellular Same as newly synthesized viral protein in cytoplasm – this is possible because MHC molecules display the internal contents of the cell on the surface
2 TUMOUR SPECIFIC VIRAL ANTIGENS and what type of cancer?
- EBV for EBV-positive lymphoma
- HPV for - Human papilloma virus-positive genital tumours (e.g. cervical cancer)
- HTLV1-associated leukaemia/lymphoma
- HepB virus- and HepC virus-associated hepatocellular carcinoma
What are tumour associated antigens
derive from normal cellular proteins which are aberrantly expressed (timing, location or quantity)
What needs to happen before an immune response against tumour associated antigen may occur
tolerance may need to be overcome
Example of tumour associated antigens? (5)
- Cancer-testes antigens (developmental antigens)
- Human epidermal growth factor receptor 2 (HER2)
- Mucin 1 (MUC-1)
- Carcinoembryonic antigen (CEA)
prostate-specific antigen (PSA), prostate-specific membrane antigen (PSMA), prostatic acid phosphatase (PAP) (normal proteins that are overexpressed in prostate tumours
5 approaches to tumour immunotherapy?
- Antibody-based therapy
- Therapeutic vaccination
- Immune checkpoint blockade
- Adoptive transfer of immune cells
- Combinations of the above
2 Problems to targeting tumour associated antigens
- If you generate a response against a TAA, you may get symptoms of AUTOIMMUNITY e.g. autoimmune depigmentation in melanoma
- Immunological tolerance – both normal tolerance, and tumour-induced tolerance
Example of a monoclonal Ab based therapy and its target
Trastuzumab (Herceptin) – anti-HER2
Problem with monoclonal Ab based therapy?
Cost
Difference between tumour specific and tumour associated antigens?
Tumour associated are normal proteins which are aberrantly expressed (timing/location/quantity) vs proteins which are inherently different (viral/mutated)
What is the one licensed cancer vaccination and how does it work
- There is one FDA approved vaccine to treat cancer (also licensed for sale in the UK, but not NICE approved) Provenge (sipuleucel-T) for advanced prostate cancer
- Patient’s own WBC are treated with a fusion protein between prostatic acid phosphatase (PAP) and the cytokine GM-CSF
- Stimulates DC maturation and enhances PAP-specific T cell responses
What is the future of cancer prevention?
PERSONALISED’ TUMOUR-SPECIFIC CANCER VACCINES (?):
What 3 pathways do IMMUNE CHECKPOINT BLOCKADE target?
- Targets CTLA-4 and PD-1 pathways
CTLA-4 is expressed on …..
activated and regulatory T cells, binds to CD80/86
CTLA-4 binds to…
CD80/86 (costimulatory molecules on APC)
CD80/86 are….
(costimulatory molecules on APC)
PD-1 is expressed on…
activated T cells
What is the concern in immune checkpoint blockade
autoimmune responses
Explain adoptive cell transfer (3 steps)
- If you can take out cells from a patient, you can expand them in vitro by stimulating them with antigen/cytokines to enhance a tumour responce
- There is the potential for introducing new molecules or including new antigen receptors by genetic engineering
- We can then expand these cells and put them back into the patient
Explain how chimeric antigen receptors work
- These are engineering receptors which graft an arbitrary specificity onto an immune effector cell (T cell)
making a completely new artificial type of T cell receptor that can recognise something being expressed on the tumour cell.
If the antibody is then activated it will cause the T cell to kill the ting
