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 advanced 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, which is important for Treg suppression. This resulted in PKCη localization in the Treg immunological synapse. These events promoted and were obligatory for 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 slow growing prostate adenocarcinoma TRAMP-C1 but, surprisingly, retained the ability to inhibit experimental autoimmune colitis, a disease that often occurs in cancer patients treated with checkpoint inhibitors. Moreover, PKCη loss in Treg cells increased the number of intratumoral CD4+ and CD8+ effector T cells without affecting Treg numbers, resulting in a significant increase of the intratumoral Teff:Treg cell ratio, a parameter considered to predict a better clinical outcome. 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. These findings establish the novel CTLA-4-PKCη signaling pathway as critical for suppressing tumor immunity, and implicate it as an attractive cancer immunotherapy target.
Citation Format: Christophe Pedros, Kok-Fai Kong, Amnon Altman. Control of regulatory T (Treg) cell function by protein kinase C-eta (PKCη): A novel target for cancer immunotherapy [abstract]. In: Proceedings of the Second CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; 2016 Sept 25-28; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(11 Suppl):Abstract nr A148.
- ©2016 American Association for Cancer Research.