I've read many reviews and papers about the resistance of immune checkpoint blockade.
Some said that the resistance is due to too much inhibitory receptors/ligands on cancer cells, which would make T cells exhaust.
Some said the opposite, that the resistance is due to too little inhibitory receptors/ligands on cancer cells, so that checkpoint blockades don't work.
So to overcome resistance against checkpoint blockade, do we want to upregulate inhibitory molecules such as PDL1, or to downregulate them?? So confused...
The main point to know (very much simplified scheme): PD-L1 is expressed by tumor cells and used by tumor cells to regulate anti-tumor CD8+ T cell responses. Thus, logically if we want to kill cancer cells we need to control/block the PD-L1 expressed by tumor cells. However, as always, it is not that simple. PD-L1 is also expressed by immune cells. And we have a very little idea why and how it all works from the point of immune cells. We (probably?) do not want to block the PD-L1 in immune cells (if PD-L1 in T cells helps to kill cancer cells), No one knows the exact answer to this question so far. If there is a lot of PD-L1 expressed by cancer cells - and very little by T cells, that is logically good and we can block the system and most likely stimulate cancer regression. There are still many "if" in this hypothesis. I have got a paper for you attached that looks at the PDL1 expression in immune cells.
Logically, you should down-regulate PD-L1. But there are other checkpoint inhibitors that you can also down-regulate... m-Antibodies are already approved by the FDA for this and other are on the clinical stage. Do your literature correctly...
... You can also down-regulate the PD-1 (PD-L1 is the ligand) as with the Nivolumab mAb inhibitor that was already approved by the FDA several years ago.
- Badges
- Science method