Tumour immunology and immunotherapy of cancer:part 1 Flashcards
What are the two major obstacles for the targeting of tumour-associated antigens in immunotherapy of cancer?
Autoimmune responses against normal tissues Immunological tolerance
What is antibody-based therapy?
- 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
Describe the effect of the PD-1 – PDL-1 signalling on the T cell response.
When a T cell has been exposed to an antigen several times, it starts to express PD-1 receptors Tumour cells the upregulate expression of the PDL-1 ligand, which can bind to the PD-1 receptor and downregulate the T cell response Blockade of the PD1-PDL1 interaction could help stimulate the T cell response
How do immune responses to tumours have some similarities with those to virus infected cells?
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
How do tumour-associated antigens differ from tumour-specific antigens?
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
Describe the cancer-immunity cycle.
Antigens are released from cancer cells and captured by APCs, which then migrate to local draining lymph nodes If the environment is sufficiently inflammatory and there is enoughcostimulation then you will get activation of the T cell response Once the T cells are activated they go back to the tumour – the processed antigens are then recognised by the T cells, which then kill the cancer cells NOTE: this cycle is pretty similar to viral infections
Describe the selection pressure that is induced by the immune response to tumours
Good immune response to tumour cells by TILs favours cells that have a mutation that allows them to “hide” from immune system
Give examples of tumour-associated antigens.
Cancer-testis antigens – silent in normal adult tissues except male germ cells MAGE – melanoma-associated antigens – identified in melanoma, also expressed in other tumours
Give two examples of opportunistic malignancies.
EBV positive lymphoma (post-transplant immunosuppression) HHV8 positive Kaposi sarcoma (occurs in HIV)
Which MHC class presents endogenous peptides?
MHC Class I
What are four possible approaches to tumour immunotherapy?
Cancer vaccination – immunisation to stimulate natural anti-cancer responses (image is shown for personilised and for therapeutic cancer vaccination: 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)
Genetic modification of T cells to express a receptor capable of recognising the tumour – these are then inserted back into the patient so that the T cells can kill the tumour cells _Blockade of molecules that inhibit T cell response_s(
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) and the other has been spoken about)
CAR:
Patient’s own WBC are treated with a fusion protein between prostatic acid phosphatase (PAP) and the cytokine GM-CSFStimulates DC maturation and enhances PAP-specific T cell responses
Which oncoproteins of HPV are responsible for the induction andmaintenance of cervical cancer?
E6 E7
What evidence is there of the importance of tumour surveillance by the immune system?
- 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)
How can breast cancer be linked to the following symptoms: severe vertigo, unintelligible speech, truncal and appendicular ataxia?
Paraneoplastic cerebellar degeneration
