Cancer

Question 1

Describe the normal system which prevents cancer from occuring and how this can cause cancer?

Answer 1

Proto-oncogenes cause the proliferation and growth of cells whilst tumour suppressor genes stops cell growth and causes apoptosis to keep cells in balance. However, multiple mutations (5 - 6 times) cause cells to over proliferate and become cancer (when mutated proto-oncogenes become oncogenes).

Question 2

What are the hallmarks of cancer?

Answer 2

Over proliferation or growth of cells
Resistance to cell death
Blood supply being created (inducing angiogenesis)
Activating invasion and metastasis
Replicative mortality (caused by growth of telomeres).

Question 3

How did they discover immune system involvement in cancer?

Answer 3

Injecting both immunodeficient and healthy mice with cancer and noticing how those with healthy immune systems where less likely to get cancer.

Question 4

Describe how cancer can immunoedit?

Answer 4

1 - Cancer initiation = a cancer cell begins to grow from non-malignant cells

2 - Elimination = tumour cell downregulates MHC-1 causing NK cells to react and destroy them.

3 - Equilibrium = tumours are dormant but if they get the correct signals from mutations can overproliferate (this includes CD4+ T cells secreting IFN gamma).

4 - Escape = the tumour progresses by upregulating MHC-1 and recruiting Tregs and MDSC cells to start dampening down body immune response so the tumour can grow.

Question 5

Describe the anti-tumour immune response?

Answer 5

Tumour cell secretes antigens T cells recognise which triggers the T cell pathway to destroy them

Question 6

How do tumours evade the immune system?

Answer 6

They downregulate MHC molecules or tumour antigens and express non-classical HLA molecules meaning the T cell can’t find them.

They could inhibit the T-cell by using inhibitory ligans when the T cell comes to find the antigen. They also secrete immuno-supressive cytokines.

Also the recruitment of Treg and MDSC can inhibit CD8+ T cells and Th1.

Question 7

What are the emerging hallmarks of cancer?

Answer 7

Immunosupression
Deregulating cellular energetics
Tumour promoting inflammation
Genome instability and mutation

Question 8

Describe monoclonal antibody treatment against solid tumours?

Answer 8

Can block growth factor receptors and deplete tumour cells expressing tumour associated antigens.

Question 9

What ways can monoclonal antibody treatment target the tumour immune response?

Answer 9

Block checkpoint inhibitors and enhance T cell function using BiTEs

Question 10

What is the mechanims of action of the monoclonal antibody treatment trastuzumab? (4 ways)

Answer 10

HER2 cleaves causing a signal transduction pathway to create tumour cells. This action can be blocked by trastuzumab.

Her2 dimorizes to other Hers before cleavage which can be blocked.

Her2 can be endocytosed causing its degradation.

Transtuzumab can bind to HER2 and also to immune effector cells initiating immune attack and tumour cell lysis

Question 11

How can rituximab be used against cancer?

Answer 11

It works against CD20 found on B-cells and can bind stopping B-cell activation and production of plasma cells.

Works for rheumatoid arthritis and B cell lymphoma

Question 12

Describe how the mechanisms of rituximab can stop B cells and tumours? (4 ways)

Answer 12

It can directly kill cells by initiating down stream signalling.

Complement dependant cytotoxicity caused by C1q binding to an Fc region on rituximab initiaing the classical pathway and cell lysis.

Antibody dependant cell cytotoxicity is caused by FCyR3 binding to rituximab-CD20 causing granzyme and perforin release killing B cells

Antibody dependant phagocytosis caused by macrophages FCgamma receptors recognising rituximab-CD20 and causing signalling pathways leading to B cell phagocytosis

Question 13

Describe how checkpoint inhibitors keep the immune response running when tumour cells try to supress it in the priming phase?

Answer 13

During the priming phase when DC and T cells exchange information a checkpoint inhibitor can bind between B7 and CTLA-4 causing immune activation. CTLA-4 is only upregulated when inflammation occurs and if binding where to happen this would stop the immune response.

Question 14

Describe how checkpoint inhibitors keep the immune response running when tumour cells try to supress it in the effector phase?

Answer 14

During the effector phase the TCR should bind to MHC however tumours upregulate PD-L1 which binds to PD-1 preventing the T-cell from activating and so checkpoint inhibitors bind to both PD1 and PD-L1 to stop this deactivation.

Question 15

What would make a tumour hot vs cold?

Answer 15

A cold tumour has no T-cells or NK cells whilst a hot tumour does. Cold tumours therefore can’t be treated with checkpoint inhibitors and prognosis is poor.

Question 16

What are BiTEs?

Answer 16

Fusion proteins containing 2 single chain variable regions from 2 different antibodies. One which binds to the T-cell (via CD3) and the other to the tumour cell (via tumour specific molecules). This pulls them close and induces T-cell signalling through the CD3.

Question 17

Do people have naturally occuring anti-tumour responses?

Answer 17

Yes they make anti-tumour T cells and we can use this to create treatments for tumours.

Question 18

How do you create autologous T cell therapy?

Answer 18

Excise the patients tumours and plate the fragments. You are looking for Hot tumours and when found culture and select the ones you need. You can then expand these and put them back in the patients and these should fight the T-cell for you.

You’d normally administer with anti-PD1 or anti-CTLA-4

Question 19

In improved autologous T cell therapy you take tumour neoantigens and see how Tcells react to them before identifying the reactive T-cell receptors - what can you do with these once found?

Answer 19

Make a neoantigen vaccine which can be normal or can contain DC to be put back into the patients.

Adoptive T cell therapy (engineer some T cells to contain these receptors) put these back into pateints and they should be able to identify and react with tumour neoagent

Question 20

How do you make chimeric antigen receptor (CART therapy)?

Answer 20

Replace the TcR in T-cells with a chimeric fusion protein of various domains by taking a FAB region of an antibody and fusing it onto a T cells receptor. This then binds antigens with a strong specificity. Then modify the receptor to have lots ofsignallingdomains by fusing intercellular signals such as CD3. This then means no co-stimulation needs to occur as the one receptor can signal for both.

Question 21

How does CAR-T therapy work?

Answer 21

Use autologous T cell therapy to retreive T-cells. Add the chimeric antigen receptor and a kill switch. Proliferate these cells and place back into patient. Once they have done their job trigger the kill switch to remove them from the system.

Question 22

How does cancer use chemokines to benefit them?

Answer 22

CCL2 is upregulated in early tumour development so tumours can gether macrophages to help promote their growth and supress the immune system.

Question 23

How can we use the cancers own chemokine system against it?

Answer 23

We can attack NK cells to the CCR2 which will then be taken into the cancer cells. This was done on mice showing a reduced cancer burden after.

Question 24

How is NK therapy done in humans?

Answer 24

Reprogramme iPSCs to secrete lots of CCR2 and then to become NK cells. This removes the need for donors. You can then put the CCR2 infused NK cells back into the patient where they will go into the tumours and destroy them.

Question 25

Do we know how to induce an anti-tumour T cell response?

Answer 25

Yes - they found that DC’s that are positive for CCR7 have more MHC and stimulate a better T-cell response.

So they used mice with tumours and found that if they gave DC’s sorted for CCR7 there is reduced tumour growth, increased T cell numbers and therefore increased survival.

Question 26

In what ways can we use chemokines to enhance tumour therapy?

Answer 26

Direct cells into tumours causing tumour cell lysis and direct cells to the lymph node to increase T-cell proliferation and improve their response against tumours.