Modulating regulatory T (Treg) cell functions to specifically promote anti-tumor immune responses is a desirable strategy for cancer immunotherapy. Blockade of checkpoint molecules, CTLA-4 and PD-1, has proven clinical efficacy in advanced metastatic melanoma and other malignancies. We recently found that protein kinase C-eta (PKCη), a member of the PKC enzyme family, physically associated with CTLA-4, an inhibitory receptor highly expressed on Treg cells, which is important for Treg cell-mediated suppression. PKCη is recruited to the Treg cell immunological synapse, and mediates contact-dependent suppression by Treg cells. PKCη-deficient (Prkch-/-) Treg cells are defective in the suppression of anti-tumor immunity against B16 melanoma but retain the ability to control the development of autoimmune colitis. Here, we extended our findings regarding the importance of the CTLA-4-PKCη complex in contact-dependent Treg cell suppressive activity to an additional tumor model, i.e., the slow growing prostate adenocarcinoma TRAMP-C1, indicating that the novel CTLA-4-PKCη signaling pathway may be relevant to a broad spectrum of solid cancers. We further found that in the tumor microenvironment, the loss of PKCη in Treg cells substantially promoted the infiltration of CD4+ and CD8+ effector T cells without affecting the Treg cell numbers. As a result, there was a significant increase in the intratumoral CD8+ to Treg cell ratio, a parameter considered to be predictive of a better clinical outcome. Thus, our data reveal that the novel CTLA-4-PKCη signaling pathway, which we identified, is critical for suppressing anti-tumor immunity and, hence, implicate this pathway as an attractive cancer immunotherapy target for a broad spectrum of clinically debilitating malignancies.
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 CRI-CIMT-EATI-AACR Inaugural International Cancer Immunotherapy Conference: Translating Science into Survival; September 16-19, 2015; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(1 Suppl):Abstract nr B051.
- ©2016 American Association for Cancer Research.