4.0 Immunotherapy Flashcards
What are the 2 main immune checkpoint inhibitor pathways?
- programmed cell death 1 pathway (PD-1 pathway)
- cytotoxic T-lymphocyte associated antigen 4
(CTLA-4 Pathway)
What is the programmed cell death receptor 1 (PD-1 receptor)?
The PD-1 receptor is expressed on the surface of activated t cells.
THe PD-1 receptor acts as a switch, to switch off unwanted “T” cell activity.
How does the PD-1 receptor switch off “T cell activity?
If “T” cells become overactive and start attacking normal healthy cells
Normal cells express a complementary molecule – The programmed Cell Death Ligand 1 (PD-L1)
PD-L1 binds with PD-1 to switch off the inappropriate cytotoxic activity of the “T’ cells
What happens in cancer cells?
PD-L1 is overexpressed on cancer cells
PD-L1 binds with PD-1
Switching off the cytotoxic effect of T Cells on the cancer cells
Allowing the cancer cells to survive and proliferate
What are the two immune check point inhibitors which effect PD-1 and PD-L1
PD-1 inhibitors e.g. Nivolumab
PD-L1 inhibitors e.g. Avelumab, Durvalumab
What is the mode of action of PD-1 inhibitors?
- PD-1 inhibitors block the PD-1 receptor
- PD-L1 is then unable to bind with the PD-1 receptor
- This means the T Cells are not switched off by PD-L1
- This Increases the chance the T Cells will detect the cancer cells and target them
- Reducing cancer cell proliferation and survival
- e.g. Nivolumab
What is the mode of action of PD-L1 inhibitors?
- PD-L1 on the cancer cell is unable to bind with PD-1 receptor on the T Cell
- The T Cell is no longer switched off
- Increasing the possibility that the T Cells will detect the cancer cells and attack them
- Reducing cancer cell and reducing proliferation
- e.g. Avelumab, Durvalumab
How are T cells activated in a healthy individual?
T cells are activated when…
CD28, A costimulatory receptor, found on the surface of T cells
binds with (CD80 & CD86) costimulatory molecules found on the surface of antigen presenting cells
What is the CTLA-4 pathway?
CTLA-4 (cytotoxic T-lymphocyte-associated protein 4) is expressed on the surface of T cells, specifically activated T cells.
It is a critical immune checkpoint receptor that functions to downregulate T cell activation and modulate immune responses.
CTLA-4 competes with the co-stimulatory receptor CD28 for binding to the ligands CD80 (B7-1) and CD86 (B7-2) on antigen-presenting cells (APCs).
When CTLA-4 binds to CD80/CD86, it sends inhibitory signals to T cells, leading to decreased T cell activation and proliferation.
This regulatory function helps to prevent excessive or uncontrolled immune responses that could lead to autoimmunity or tissue damage.
How is the CTLA-4 pathway compromised in cancer?
Tumors use the CTLA-4 pathway to try and evade immune surveillance and the associated anti tumour immune response by T cells.
They do this by increasing CTLA-4 expression or expressing CTLA-4 ligands, inhibiting T cell activation and anti-tumor immune responses.
Which type of drugs target the CTLA-4 inhibitors?
CTLA-4 inhibitors
What is the mode of action of CTLA-4 inhibitors?
CD28 binds with CD80/CD86 ligands on antigen presenting cells including cancer cells, which activate T Cells, which could potentially target cancer cells.
In cancer, CTLA-4 competes with CD28 to bind to the CD80/86 ligands, blocking in the activation of T Cells.
CTLA-4 inhibitors block the ability of CD80/86 ligands from binding with CDLA-4, which results in the CD80/86 ligands binding with CD28 on the T cell, activating the T cell.
Exposing the tumour to a potential immune attack from T Cells.
