Tumour Immunology

Question 1

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

Answer 1

Paraneoplastic cerebellar degeneration

Question 2

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

Answer 2

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 (CDR2) 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

tells us that tumours can express antigens normally absent or in immunological privileged sites in moral human tissue, immune system detects and launches an attack on the abnormally expresses antigen/tumour which may result in auto-immune destruction of normal tissue.

Question 3

Describe the cancer-immunity cycle.

Answer 3

1. Cancer cells release cancer-specific antigens
2. APC’s take up the cancer antigens
3. APC’s prime the T-cells in the lymph nodes to the antigens
4. T-cells migrate to tumour (CTLs)
5. T-cells infiltrate tumour (Tumour Infiltrating Lymphocyte, TILs)
6. T-cells recognise tumour
7. T-cells kill tumour
   - cycle repeats as cellular contents released
   - results in in immune selection pressure which can lead to loss of tumour MHC expression like how bacteria avoid anitbiotics

Question 4

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

Answer 4

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 5

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

Answer 5

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 6

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

Answer 6

Local inflammation in the tumour

Expression and recognition of tumour antigens

Question 7

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

Answer 7

It takes a tumour a while to cause inflammation

Antigenic differences between normal and tumour cells can be very subtle

Question 8

Which MHC class presents endogenous peptides?

Answer 8

MHC Class I

Question 9

Give two examples of opportunistic malignancies.

Answer 9

EBV positive lymphoma (post-transplant immunosuppression)

HHV8 positive Kaposi sarcoma (occurs in HIV)

Question 10

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

Answer 10

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

Question 11

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

Answer 11

E6

E7

Question 12

What proteins do the vaccines for HPV use?

Answer 12

Structural proteins are used to generate virus particles

Question 13

Give an example of an HPV vaccine.

Answer 13

Gardasil

Question 14

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

Answer 14

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

Question 15

What are tumour-associated antigens?

Answer 15

They are generally derived from normal cellular proteins which are abberantly/abnormally expressed.
Since they are normal self proteins tolerance may need to be overcome

Question 16

Give examples of tumour-associated antigens.

Answer 16

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 17

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

Answer 17

Tumour-associated antigen – when it is over-expressed

Tumour specific antigen – when it becomes mutated

Question 18

Describe the problem with tolerance in cancer immunotherapy.

Answer 18

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

Question 19

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

Answer 19

1. Autoimmune responses against normal tissues
2. Immunological tolerance (sometimes tumour cells expressing the antigen can induce tolerance as they may not cause inflammation so the presentation of antigens without co-stimulation could make t-cells anergia and induce tolerance)

Question 20

What are four possible approaches to tumour immunotherapy?

Answer 20

1. Therapeutic vaccination
2. Antibody-based therapy
3. Immune checkpoint blockade
4. Adoptive transfer of immune cells

Question 21

What percentage of the population develops immunity to HPV-16 infection?

Answer 21

99%

Other 1% may develop cervical neoplasia of this 1% half have no immunity and the other half have non functional immunity

Question 22

List four more example of TAA’s

Answer 22

HER2- over expressed in some breast cancer
MUC-1- over expressed in many cancers
CEA- normally only expressed in foetal/embryo, over expressed in cancer
Prostate antigens- PSA, PMSA, PAP

Question 23

What is tyrosinase and what is its relevance in immunotherapy.

Answer 23

Enzyme in rate limiting step in production of melanin.
In treatment of melanoma, t-cells target cancer cells and tyrosinase so there is a loss of skin pigmentation- vitiligo
(immune response leads to symptoms of autoimmunity)

Question 24

List and give examples of the three types of monoclonal antibody based therapy (immunotherapy)

Answer 24

1. Naked, direct antibody e.g Anti-HER2 antibody- HERCEPTIN
2. Conjugated, antibody + radioactive particle/drug e.g Anti-CD20 linked to yttrium-90- ZEVALIN used in non- Hodgkin lymphoma and Anti-HER2 linked to cytotoxic drugs- KADCYLA
3. Bi-specific antibodies, multiple direct antibodies e.g Anti-CD3 & Anti-CD19

Question 25

State an example of a drug used in therapeutic cancer vaccination (immunotherapy) and how it works

Answer 25

PROVENGE (only approved drug) for advanced prostate cancer Patients WBC treated w fusion protein of PAP and cytokine GM-CSF, this stimulated DC (are antigen presenting cells) maturation and enhances PAP specific T-cell responses

Question 26

Give examples of drugs used in immune checkpoint blockade (immunotherapy)

Answer 26

This reduces/removes regulatory controls of existing t-cell repossess thus enhancing the patients response to the cancer. 1. Anti CTLA-4, IPLIMUMAB Cancer cells produce antigens, which the immune system can use to identify them. These antigens are recognized by dendritic cells that present the antigens to cytotoxic T lymphocytes (CTLs) in the lymph nodes. The CTLs recognize the cancer cells by those antigens and destroy them. However, along with the antigens, the dendritic cells present an inhibitory signal. That signal binds to a receptor, cytotoxic T lymphocyte-associated antigen 4 (CTLA-4), on the CTL and turns off the cytotoxic reaction. This allows the cancer cells to survive.[4] Ipilimumab binds to CTLA-4, blocking the inhibitory signal, which allows the CTLs to destroy the cancer cells 2. Anti PD-1, NIVOLUMAB (many cancer cells make PD-L1/L2, preventing this binding to PD-1 allows t-cells to carry on working, normally binding inactivates them to prevent overreaction)

Question 27

State where the two receptors targeted in immune checkpoint blockade are expressed and their functions.

Answer 27

CTLA-4, expressed on activate T-regulatory cells and binds to CD80/86 (which are co-stimulatory molecules on APC'S) PD-1 expressed on activated T-cells, binds to PD-L1/L2

Question 28

Explain how the adoptive transfer of cells works in immunotherapy

Answer 28

Tumour may be removed during surgery | Extract TIL's and then multiply their number before re-infusing into patient.

Question 29

What are tumour specific antigens

Answer 29

Protein expressed via onco-proteins and are not normally found in the body made in tumours

Question 30

What is the circumstantial evidence for immune control of tumours?

Answer 30

1. Microscopic colonies of cancer cells have been found in people that are controlled well and do not develop 2. Patients treated for melanoma that are free from disease that become organ donors can induce melanoma in the donor receipts, so donor had some immunity to melanoma 3. Deliberate immunosuppression leads to increased risk of malignancy 4. Men have a 2x higher chance of dying from cancer than women who typically mount stronger immune responses)