Control of regulatory T (Treg) cell function by protein kinase C-eta (PKCη): A novel target for cancer immunotherapy

Abstract

Abstract Modulating regulatory T cell (Treg) function to promote anti-tumor immunity is a desirable strategy for cancer immunotherapy. Blockade of checkpoint molecules CTLA-4 and PD-1 has shown clinical efficacy in metastatic melanoma and other malignancies. We recently reported that Treg stimulation induced the recruitment of protein kinase C-eta (PKCη), together with the GIT-PAK-PIX signaling complex that mediates focal adhesion disassembly, to CTLA-4, an inhibitory receptor highly expressed on Foxp3+ Tregs and important for Treg suppression. As a result, PKCη was recruited to the immunological synapse of stimulated Treg. These events promoted Treg-mediated contact-dependent suppression, including suppression of tumor immunity, via a mechanism likely involving depletion of costimulatory CD80/86 ligands from APCs (Nat Immunol. 2014;15:465–72). PKCη-deficient (PKCη−/−) Tregs were defective in the suppression of anti-tumor immunity against B16 melanoma and the prostate adenocarcinoma TRAMP-C1 but retained the ability to inhibit experimental colitis, a disease that often occurs in patients treated with anti-CTLA-4 antibodies. PKCη loss in mouse Treg cells increased both the number of intratumoral CD4+ and CD8+ effector T cells and their ability to produce cytokines upon restimulation. Moreover, shRNA-mediated knockdown of PKCη reduced the suppressive activity of human Tregs. Impaired activation of the GIT-PAK-PIX complex and the resulting defect in CD80/86 depletion are likely responsible for the defective suppressive activity of PKCη−/− Tregs. Altogether, our findings establish the CTLA-4-PKCη signaling pathway as critical for suppressing tumor immunity, and implicate it as an attractive cancer immunotherapy target.