Cancer immunity cycle

Question 1

What is the route of MHCI presentation?

Answer 1

Endogenous antigen gets degraded in the proteasome in the cytosol. Degraded endogenous antigen gets translocated into the ER lumen by TAP. Antigen gets loaded onto MHCI and placed on the cell membrane.

Question 2

What is the route of MHCII presentation?

Answer 2

Exogenous antigen gets degraded via the lysosomal pathway and loaded onto MHCII. MHCII and the antigen get placed on the cell membrane.

Question 3

What is the “E” hypothesis?

Answer 3

Elimination, equilibrium and escape of cancer cells from the immune system

Question 4

What are the steps of the cancer immunity cycle?

Answer 4

1. Release of cancer cell antigens (cancer cell death)
2. Cancer antigen presentation (DCs/APCs)
3. Priming and activation (DCs and T-cells)
4. Trafficking of T-cells to site of the tumour(s) (CTLs)
5. Infiltration of T-cells into tumour(s) (CTLs, endothelial cells)
6. Recognition of cancer cells by T-cells (CTLs, cancer cells)
7. Killing of cancer cells (Immune cells and cancer cells)

Question 5

What are the three types of unwanted TMEs (in relation to T-cells present)?
What is needed to fix them?

Answer 5

Immune desert: T-cells are absent from the tumour and TME. You need to generate active and tumour-specific T-cells
Immune excluded: T-cells have accumulated, but are not efficiently infiltrating the TME. The T-cells need to infiltrate the TME.
Inflamed: T-cells have infiltrated the TME, but are not functioning properly. The T-cells need to kill the tumour.

Question 6

What are the 3 key bottlenecks in inducing a CTL response against cancer?

Answer 6

Central tolerance: There should be tumour-specific T cells in the peripheral repertoire. The tumour must offer recognizable (non-self) antigens.

Peripheral tolerance: To kickstart and (most likely) to perpetuate the T cell response, the tumour must activate dendritic cells. This usually does not happen.

Tumour-associated immune suppression: CTLs are suppressed in tumour microenvironment (TME)

Question 7

We need suitable antigen targets to make a cancer cell visible to the adaptive immune system (=immunogenic). How can this be done?

Answer 7

Viral proteins (HPV, EBV)
Mutated peptides (neo-antigens)
Cancer-testis antigens (NY-ESO-1, MAGE-A3)
Other alterations (e.g. post-translational modifications, oncogenes)
Increased expression compared to self (MART-1, gp100, tyrosinase)