Tumour Immunology

Question 1

Describe an experiment to demonstrate the immunogenicity of tumours.

Answer 1

• A mouse injected with a carcinogen will develop a tumour.
• If cells from this tumour are transplanted into another mouse, this mouse will develop the same tumour as expected.
• However if cells from a mouse with the tumour are taken and irradiated (so that the tumour cell can no longer replicate), and then transplanted into another mouse, that mouse will develop resistance to developing that cancer if it is challenged with a tumour cell.

Another way of demonstrating the same thing:

• If a tumour is surgically removed from a mouse such that it is completely free of the tumour, and it is then later treated with cells from the removed tumour, it will not develop the tumour again.

Question 2

In mice models, which cells were required for the tumour to induce an immune response?

Answer 2

T cells.

Question 3

What is cancer immunosurveillance?

Answer 3

The concept that the immune system can recognise precursors of cancer and, in most cases, destroy these precursors before they become clinically apparent.

Question 4

What is cancer immunoediting?

Answer 4

• The concept that the immune system edits the immunogenicity of tumours by a process of natural selection that may eventually result in the formation of a tumour. It consists of the 3 Es:

1 - Elimination - immune-mediated destruction of most cancer cells.

2 - Equilibrium - a dynamic equilibrium between the immune system and any tumour cell that has survived the elimination phase. The immune response is enough to contain, but not eliminate, these cells.

3 - Escape - the tumour cell variants selected in equilibrium now grow out in an immunologically intact environment.

Question 5

List the signals required for a T cell to become activated.

Answer 5

1 - A first signal is recognised through the T cell receptor in the form of a protein presented on MHC on an antigen-presenting cell.

2 - A second costimulatory signal is required that can be delivered by a number of molecules on the surface of a T cell interacting with molecules on the surface of an antigen-presenting cell.

Question 6

Give an example of an interaction between molecules on the surface of a T cell and molecules on the surface of an antigen-presenting cell to produce a costimulatory signal.

Answer 6

CD80 and CD86 on the surface of antigen presenting cells often interacts with CD28 on the surface of T cells.

Question 7

Describe the process of generating an immune response to a tumour.

Answer 7

1 - Tissue damage at the site of a tumour results in tumour antigen release.

2 - A dendritic cell presents this tumour antigen.

3 - The dendritic cell travels to a lymph node and presents the antigen to many T cells.

4 - The T cells whose T cell receptors recognise the tumour antigen on the dendritic cell undergo clonal expansion.

5 - The selected T cells leave the node and enter the circulation to travel to the site of the tumour, where they elicit an immune response.

Question 8

List 5 mechanisms that explain why tumours originating in the body are not protected by tolerance to self antigens.

Answer 8

1 - Some proteins might become mutated during the formation of the cancer, such that they are no longer recognised as self antigens.

2 - Some normal self antigens might be overexpressed, resulting in an immune response to those antigens.

3 - Lineage-specific antigens might be inappropriately expressed in the tumour. Although these are self, an immune response is generated at the expense of damage to that lineage.

4 - Abnormal post-translational modification of self proteins in the tumour.

5 - The tumour carries a viral protein.

Question 9

List 3 examples of normal self antigens that can be overexpressed in tumours, resulting in an immune response.

Answer 9

1 - Oncofoetal antigens which are normally expressed in embryogenesis, such as CEO and AFP.

2 - Cancer-testis antigens (MAGE) in melanomas.

3 - Telomerase.

Question 10

List 4 lineage-specific antigens that can be inappropriately expressed in tumours to cause an immune response.

In which cancers are these antigens overexpressed?

Answer 10

In melanomas:

1 - Mart1 / Melan A complex.

2 - Gp100.

3 - Tyrosinase.

In B cell lymphomas:

4 - Surface immunoglobulins.

Question 11

Give an example of an antigen that can be abnormally modified post-translationally to cause an immune response.

In which cancers is expression of this antigen implicated?

Answer 11

• Underglycosylated mucin.

1 - Breast cancer.

2 - Pancreatic cancer.

Question 12

List 2 oncogenic viruses.

Which tumours do they cause?

Answer 12

1 - HPV.

• Cervical cancer.

2 - EBV.

• Hodgkin’s lymphoma.
• Nasopharyngeal carcinoma.

Question 13

How can an immune response destroy a tumour without targeting the tumour cells directly?

Answer 13

By targeting the tumour stroma, e.g. by identifying endothelial markers.

Question 14

List 4 characteristics of a good target antigen for tumour immunotherapy.

Answer 14

1 - The antigen is tumour-specific (reduces toxicity of the immune response).

2 - The antigen is shared amongst other tumour types (the treatment is widely applicable).

3 - The antigen is critical for tumour growth / survival (to ensure there is a lack of antigen-loss tumour cell variants).

4 - There is a lack of immunological tolerance to the tumour tissue (to ensure that there maximally high avidity T cells are produced).

Question 15

List 3 good examples of tumour antigens that are highly tumour-specific.

Answer 15

1 - Mutated self-proteins.

2 - Viral antigens.

3 - Cancer-testis antigens.

Question 16

List 2 good examples of tumour antigens that are commonly shared amongst other tumour types.

Answer 16

1 - Mutated self or vital proteins involved in oncogenesis.

2 - Lineage-specific antigens (for multiple tumours within this lineage).

Question 17

List 2 good examples of antigens that are critical for tumour growth / survival.

Answer 17

1 - Mutated self or viral proteins involved in oncogenesis.

2 - Overexpressed self proteins such as telomerase.

Question 18

List 2 good examples of tumour antigens to which an individual will have a lack of immunological tolerance.

Answer 18

1 - Mutated self proteins.

2 - Viral antigens.

Question 19

How do adhesion molecules on the surface of T cells and antigen-presenting cells contribute to the activation of T cells?

Answer 19

The adhesion molecules stabilise the interaction between the T cell and the antigen-presenting cell.

Question 20

List 6 mechanisms by which tumours might escape an immune response.

Which tumours are associated with these mechanisms?

Answer 20

1 - Loss of HLA class I expression in the tumour cells (e.g. in lung cancer, prostate cancer and melanoma).

2 - Reduced expression of other molecules involved in antigen processing and presentation in the tumour cells (e.g. in colorectal cancer).

3 - Loss of costimulatory molecule expression between the T cell and the tumour.

4 - Loss of adhesion molecule expression in the tumour cells.

5 - Loss of the target antigen in tumour cells (e.g. in melanoma).

6 - Inhibiting T cell infiltration.

• Remember the tumour cells must present the antigen for the T cell to recognise and attack it.

Question 21

List 2 mechanisms by which tumours inhibit T cell infiltration.

Answer 21

1 - Endothelin B receptor expression in the tumour endothelium signals to prevent the modulation of ICAM, and thereby reduces T cell adhesion to the endothelium.

2 - Nitrosylation of chemokines can keep T cells from entering the tumour core.

Question 22

List 3 mechanisms by which tumour cells can suppress an immune response.

Answer 22

1 - TGF beta is an immunosuppressive cytokine for T cells that induces Treg cells and is overexpressed in some tumours, preventing T cell action at the tumour site.

2 - IDO is a protein expressed by tumours that catabolises tryptophan, which is important for T cell function.

3 - Tumours can express factors that inhibit differentiation, maturation and function of local dendritic cells.

Question 23

What are myeloid-derived suppressor cells?

Answer 23

• A heterogeneous population of cells of myeloid origin that can expand in some tumours.
• It consists of:

1 - Myeloid progenitor cells.

2 - Immature macrophages.

3 - Granulocytes.

4 - Dendritic cells.

• It is a potent suppressor of T cell function, as they can induce Tregs and also show upregulated expression of immune suppressive factors such as arginase 1 and iNOS.
• Arginase 1 catabolises arginine, which is necessary for T cell function.
• iNOS generates nitric oxide which inhibits T cell function and induces apoptosis.

Question 24

List 3 methods of developing a T cell-based therapy for cancer.

Answer 24

1 - Nonspecific T cell stimulation.

2 - Vaccination (still being tested).

3 - Adoptive T cell therapy.

Question 25

List 2 methods of inducing non-specific T cell stimulation as a therapy for cancer. Which cancers are these methods effective for?

Answer 25

1 - Immunostimulatory cytokines such as IL2 for melanoma and renal cell carcinoma. 2 - Blockade of immunological checkpoints that naturally inhibit T cell activation. - Examples of these blockers include monoclonal antibodies ipilimumab for CTLA4 and pembrolizumab and nivolumab for PD1.

Question 26

List 3 types of tumour vaccines currently being tested.

Answer 26

1 - Irradiated tumour cells. 2 - Protein antigens. 3 - Dendritic-cell based vaccines.

Question 27

What is adoptive T cell therapy? When is it given? What is the risk of this therapy?

Answer 27

- Infusing whole donor T cell populations into cancer patients. - It is sometimes given after bone marrow transplant from the same donor of bone marrow. - There is a risk of graft vs host disease, as the T cells are allogeneic.

Question 28

List 2 methods of minimising the risk of adoptive T cell therapy.

Answer 28

1 - By infusing selected, tumour-specific T cells from a donor. 2 - By removing the cancer patient's T cells, expanding and activating them in vitro, and reinfusing them into the patient.

Question 29

What are tumour-infiltrating lymphocytes (TILs)? How are they used to treat tumours? Which tumour is most commonly treated this way?

Answer 29

- Colonies of lymphocytes found in tumours that are ineffective at destroying the cancer cells. - They can be removed from the tumours, and the tumour-specific tumour-infiltrating lymphocytes (TILs) can be selected and grown in vitro. - They are then reinfused to the tumour in high doses. - Melanoma is most commonly treated this way.

Question 30

List 2 reasons why non-myeloablative conditioning is given to a patient before TIL therapy.

Answer 30

1 - It creates space in the haematopoietic system, enabling the TILs to engraft more effectively. 2 - It depletes Treg cells, reducing immunosuppression.

Question 31

How can genetic engineering be used to treat cancer?

Answer 31

1 - A T cell that is known to have a T cell receptor against the tumour is extracted from the patient. 2 - The genes coding for the T cell receptor are replicated and placed into a virus. 3 - The virus infects other T cells (still in vitro) and incorporates the T cell receptor gene, so that the infected T cells express T cell receptors against the tumour antigens. 4 - These TCR-modified T cells are reinfused into the patient.

Question 32

Why might TIL therapy cause vitiligo? What about blindness and deafness?

Answer 32

- TIL therapy might cause vitiligo because the antigens targeted by selected TILs are shared between other healthy melanocytes. - Other antigens are shared between tissue of the eye, and others are shared between the inner ear. These antibodies can cause blindness / deafness.

Question 33

List 6 mechanisms by which monoclonal antibodies can destroy tumour tissue.

Answer 33

1 - Ipilimumab and pembrolizumab can be directed towards checkpoints that naturally inhibit T cell activation (as previously mentioned). 2 - Rituximab can be directed towards CD20, activating the complement cascade. 3 - Rituximab can also mediate antibody-mediated cellular cytotoxicity, where the antibody can mark the tumour cell for destruction by NK cells. 4 - Erbitux and herceptin can inhibit the binding of ligands to growth factor receptors, blocking proliferation through inhibition of MAPK / PI3K / Akt signalling and inducing apoptosis. 5 - Avastin can block the interaction between VEGF and its receptors, inhibiting angiogenesis. It is often coadministered with other chemotherapeutic drugs. 6 - Zevalin and bexxar are antibodies linked to a radionuclide.

Question 34

Why is avastin often coadministered with other chemotherapeutic drugs?

Answer 34

- Because avastin normalises the vasculature supplying tumours. - This makes delivery of other chemotherapeutic drugs easier, as the abnormal vasculature typically seen in tumours is ineffective at supplying the tumour with chemotherapeutic drugs.