Understanding the cellular and molecular mechanism of anti-CTLA4 mediated tumor rejection

Abstract

Abstract Although the clinical success of checkpoint inhibitors treatment is significant to prolong the patient survival, there is a substantial gap in our understanding of their mechanism in patients due to several technical and ethical limitations. Recent work suggests that the therapeutic effect of anti-CTLA-4 antibodies may not only block CTLA-4 interaction with its ligands, but also selectively deplete intratumoral Tregs (the highest expresser of CTLA-4) through ADCC. This releases the immunosuppressive state of the tumor microenvironment, thereby, promoting the expansion of effector CD4 and CD8, and increasing the secretion of IFN-g and TNF to reject the tumors. We observed a rapid Treg reduction characterized with fragile phenotype as early as 24 hours after anti-CTLA4 treatment. Using FOXP3-DTR mice, we confirmed that Treg depletion is the major contributor against tumor progression as anti-CTLA4 effect was abrogated in the DT-treated mice, and Treg function was maintained in the FcR KO mice. This suggested that FcR engagement is responsible for the Treg weakness. We hypothesized that there might be additional signal being transmitted when anti-CTLA4 is engaging with FcR which is capable of inducing Treg reduction. We made this hypothesis when we found the important receptor CD25 expressed on the Treg was significantly decreased after engagement. This receptor can also sense surrounding IL2 to maintain Treg cell survival, function, and proliferation. Interestingly, the CD25 expression was not inhibited when lacking FcR to induce CTLA4 engagement. Hence, there is still a need to study the underlying mechanism to see why Treg cells express lower CD25 after CTLA4 engagement.