Tumour immunology and immunotherapy of cancer COPY

Question 1

What proteins do the vaccines for HPV use?

Answer 1

Structural proteins are used to generate virus particles

Question 2

How might the tyrosinase enzyme be used in cancer immunotherapy, and what are its side effects

Answer 2

It generally develops poor self-tolerance It is expressed in many melanomas Can direct immune response against it.Local auto-immune depigmentation in melanoma patients

Question 3

What are four possible approaches to tumour immunotherapy?

Answer 3

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

Question 4

When is p53 considered a tumour-associated antigen and when isit considered a tumour specific antigen?

Answer 4

Tumour-associated antigen – when it is over-expressed Tumour specific antigen – when it becomes mutated

Question 5

How can breast cancer be linked to the following symptoms: severe vertigo, unintelligible speech, truncal and appendicular ataxia?

Answer 5

Paraneoplastic cerebellar degeneration

Question 6

What are the two major obstacles for the targeting of tumour-associated antigens in immunotherapy of cancer?

Answer 6

Autoimmune responses against normal tissues Immunological tolerance

Question 7

Describe the selection pressure that is induced by the immune response to tumours

Answer 7

Good immune response to tumour cells by TILs favours cells that have a mutation that allows them to “hide” from immune system

Question 8

What are tumour-associated antigens?

Answer 8

Tumour-associated antigens (TAA) derive from normal cellular proteins which are aberrantly expressed (timing, location or quantity).

Because they are normal self proteins, for an immune response to occur tolerance may need to be overcome

Question 9

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

Answer 9

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 10

Describe the effect of the PD-1 – PDL-1 signalling on the T cell response.

Answer 10

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

Question 11

What are the main problems with the immune surveillance of cancer?

Answer 11

It takes a tumour a while to cause inflammation Antigenic differences between normal and tumour cells can be very subtle

Question 12

Give two examples of opportunistic malignancies.

Answer 12

EBV positive lymphoma (post-transplant immunosuppression) HHV8 positive Kaposi sarcoma (occurs in HIV)

Question 13

What is immune checkpoint blockade?

Answer 13

• 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

Question 14

Describe the cancer-immunity cycle.

Answer 14

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

Question 15

What is antibody-based therapy?

Answer 15

• 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 16

What are the two different times at which vaccines can be given?

Answer 16

Preventative vaccination (before the disease) Therapeutic vaccination (try to control the disease once it has occurred)

Question 17

What are the requirements for activation of an adaptive anti-cancer immune response?

Answer 17

Local inflammation in the tumour Expression and recognition of tumour antigens

Question 18

Which MHC class presents endogenous peptides?

Answer 18

MHC Class I

Question 19

What is the main difference between tumours and viral infections with regards to the immune response?

Answer 19

Viral infections trigger a lot of inflammation, which causes upregulation of costimulatory molecules so an immune response can take place Tumours do not cause very much inflammation, especially early on so they are more likely to be missed by the immune system

Question 20

Give a few examples of viral infections that can cause cancer inimmunocompetent individuals.

Answer 20

HTLV1 associated leukaemia/lymphoma HepB virus- and HepC virus-associated hepatocellular carcinoma HPV positive genital tumours

Question 21

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

Answer 21

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 22

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

Answer 22

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 23

What are tumour-associated antigens? Give examples

Answer 23

• 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 24

Give an example of an HPV vaccine.

Answer 24

Gardasil

Question 25

Give examples of tumour-associated antigens.

Answer 25

Cancer-testis antigens – silent in normal adult tissues except male germ cells MAGE – melanoma-associated antigens – identified in melanoma, also expressed in other tumours

Question 26

Describe the problem with tolerance in cancer immunotherapy.

Answer 26

T cells that react strongly with self are deleted (central tolerance) so most people have tolerance against tumour-associated antigens

Question 27

Explain how breast cancer can lead to the degeneration of the cerebellum.

Answer 27

The antigen that the immune response is directed against is normally expressed in neural tissue It is only expressed in breast tissue when there is a tumour The abnormal expression of this antigen in the breast was noticed and an immune response was mounted, which then also reacted with the normal antigens in the neural tissue –> destruction of purkinje cells in the cerebellum

Question 28

Which oncoproteins of HPV are responsible for the induction andmaintenance of cervical cancer?

Answer 28

E6 E7