Tumour Immunology

Question 1

How can breast cancer be linked to: 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

Antigen the immune response is directed against is normally expressed in neural tissue (only expressed in breast tissue when tumorous)
Abnormal expression of this antigen in the breast triggered an immune response, which then also attacked the normal antigens in neural tissue –> destruction of purkinje cells in the cerebellum

Question 3

Describe the cancer-immunity cycle.

Answer 3

Tumour cells die/ release antigens
Antigens are captured by APCs, which then migrate to local draining lymph nodes
If environment is sufficiently inflammatory + there is enough co-stimulation there will be activation of the T cell response
Once activated T cells return to the tumour– the processed antigens are recognised + killed by the T cells (releasing more antigens thus the cycle continues)

Question 4

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

Answer 4

After repeated exposure to an antigen, T cell starts to express PD-1 receptors
Tumour cells upregulate expression of PDL-1 ligand, which can bind PD-1 receptor + downregulate the T cell response
Blockade of PD1-PDL1 interaction could help stimulate the T cell response
(removal of the negative regulator= immune checkpoint blockade)

Question 5

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

Answer 5

Viral infections trigger lots of inflammation, causing upregulation of co-stimulatory molecules so an immune response can take place
Tumours don’t cause much inflammation, especially early on so 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 - “danger signal”

Expression + recognition of tumour antigens

Question 7

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

Answer 7

Takes a tumour a while to cause inflammation

Antigenic differences between normal + tumour cells can be very subtle

Question 8

Which MHC class presents endogenous peptides?

Answer 8

MHC Class I

Question 9

Give 2 examples of opportunistic malignancies.

Answer 9

EBV positive lymphoma (post-transplant immunosuppression)

HHV8 positive Kaposi sarcoma (occurs in HIV)

Question 10

Give 3 examples of viral infections that can cause cancer inimmunocompetent individuals.

Answer 10

HTLV1 associated leukaemia/lymphoma
HepB virus- + 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

Surface proteins are used to generate virus like particles

Question 13

Give an example of an HPV vaccine.

Answer 13

Gardasil 9

Question 14

What are the 2 different times at which vaccines can be given?

Answer 14

Prophylactic vaccination (before disease) 
Therapeutic vaccination (to control disease once it has occurred)

Question 15

What are tumour-associated antigens?

Answer 15

Normal cellular proteins which are aberrantly expressed (wrong location/ time/ quantity) in the tumour
Immune system needs to overcome tolerance to respond

Question 16

Give 2 examples of tumour-associated antigens.

Answer 16

Cancer-testis antigens (developmental): 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 2 major obstacles for the targeting of tumour-associated antigens in immunotherapy of cancer?

Answer 19

Autoimmune responses against normal tissues  
Immunological tolerance (not having self-reactive repertoire available to begin with or tumour inducing tolerance by releasing down regulatory factors)

Question 20

What are 4 possible approaches to tumour immunotherapy?

Answer 20

Antibody- based therapy
Therapeutic vaccination
Immune checkpoint blockade
Adoptive transfer of immune cells
(combinations of any of the above)

Question 21

List 4 examples that evidence immune control of tumours

Answer 21

Microscopic tumours in healthy adults causing no symptoms
Recipients of organs from cured melanoma patients develop melanoma
Immunosuppression increases risk of malignancy
Men twice as likely to die from cancer than women- women have a stronger immune response

Question 22

In what case may the cancer immunity cycle be ineffective?

Answer 22

Any tumour cell that survives immune recognition e.g. via MHC down regulation, will be selected for, proliferate + escape immune destruction

Question 23

What is the function of MHC class I and II?

Answer 23

I (all nucleated cells): Present endogenous antigens that originate from cytoplasm
II (on APCs): Present degraded peptide of pathogen antigen

Question 24

What is a tumour specific antigen?

Answer 24

Antigen only found in tumour cells

Question 25

Give 3 examples of tumour specific antigens

Answer 25

Viral proteins e.g. EBV, HPV
Mutated cellular proteins e.g. TGF-B receptor
Chromosomal translocations e.g. Bcr-Abl

Question 26

Give an example of proteins that are overexpressed in men and women respectively

Answer 26

Men: Prostate specific antigen (PSA) = prostate carcinoma
Women: Human epidermal growth receptor 2 (HER2)= breast carcinoma

Question 27

Give 3 types of monoclonal antibody based therapy

Answer 27

Naked (antibody by itself) e.g. Herceptin anti HER2 against breast cancer
Conjugated (antibody bound to radioactive particle/ drug) e.g. Kadcyla anti HER2 linked to cytotoxic drug
Bi-specific (GM to combine 2 specificities) e.g. anti CD3 + CD19 used in B cell tumours

Question 28

Give an example of therapeutic cancer vaccination that is also an example of adoptive transfer of cells

Answer 28

Provenge (prostate cancer)
WBCs from patient treated with fusion protein between TAA + a cytokine
Stimulates DCs to enhance T cell response to TAA
Cells vaccinated into patient

Question 29

What is immune checkpoint blockage in cancer therapy? What could this lead to?

Answer 29

Aims to reduce negative regulatory controls of existing T cell responses
Could lead to AI disease

Question 30

What is adoptive transfer of cells?

Answer 30

Source T cells from patient
Expand in-vitro by using cytokines
Re-infuse into patients to boost number of anti-tumour T cells

Question 31

What is enabled by use of Chimeric Antigen Receptors?

Answer 31

When CART binds molecule the antibody recognises, it activates T cells, as it gives signals in the form of tyrosine phosphorylation + co-stimulation