I’ve been studying the role of CTLA4 in Tregs and it’s APC ligand suppression functions....so basically here is how I read it:
Antigens are processed by antigen presentation cells. They express ligands that latch with CD8+T cells for completing the circuit to allow the antigen presentation mechanism to happen with killer T cells... CD8+T. However Tregs regulate reactions to self antigens. They have a higher affinity to recognize self antigens. To induce tolerance they use CTLA4 to absorb ligands on the Antigen presenting cells to prevent self antigen presentations to killer Tcells and prevent autoimmune disease.
Cancer was once a normal cell and still has more normal self antigens in a higher ratio than cancer specific antigens. Thus when a APC finds a cancer specific antigen on a cancer cell...the Tregs come along and see only the self antigens on the cancer cell and go “hold on there APC....you are about to initiate an attack on a normal cell”. The Treg then uses CTL4 to then take away the ligands the APC was about to use to turn on the CD8+T cells. This, of coarse, is in error.
Now comes the need for IPI...Merck’s anti-CTLA4 drug. It’s designed to block CTLA and prevent Tregs from sticking their nose into a cancer recognition process. This comes at a price. You just turned off the Tregs ability to regulate autoimmune reactions. It doesn’t decrease Tregs....just makes them less effective at regulation.
So here is wisdom: PV-10/Opdivo or Keytruda/IPI triple combo. PV-10 to expose the cancer specific antigens through necrosis, anti-PD-1 to prevent cancer cells PD-L1 ligand from engaging the CD8+T PD-1 off buttons, and anti-CTLA4 to prevent Treg from ripping off the APC ligands needed to activate CD8+T cells.