Abstract A211: Requirement of Treg-intrinsic CTLA4-PKCeta signaling pathway for suppressing tumor immunity

Abstract

The ability of Tregs to control the development of immune responses is essential for maintaining immune system homeostasis. However, Tregs also inhibit the development of efficient antitumor immune responses. Here we explored the characteristics and mechanistic basis of the Treg-intrinsic CTLA4-PKCη signaling pathway that we recently found to be required for contact-dependent Treg-mediated suppression. We show that PKCη is required for the Treg-mediated suppression of tumor immunity in vivo. The presence of PKCη-deficient (Prkch-/-) Tregs in the tumor microenvironment was associated with a significantly increased expression of the costimulatory molecule CD86 on intratumoral CD103+ DCs, enhanced priming of antigen-specific CD8+ T-cells, and greater levels of effector cytokines produced by these cells. Tumor development was reduced similarly in Treg-specific (Prkch-flox x Foxp3-Cre) and globally deficient recipients (Prkch-/-) as compared to wt mice, indicating that PKCη expression by effector cells is dispensable for the development of efficient anti-tumor responses. Similar to mouse Tregs, the GIT-PAK-PIX complex also operated downstream of CTLA4 and PKCη in human Tregs, and GIT2 knockdown in Tregs promoted antitumor immunity. We are now exploring the therapeutic impact of PKCη deletion in tumor-bearing mice using tamoxifen treatment of Prkch-flox x Foxp3-ERT2Cre and Prkch-flox x UBC-ERT2Cre mice as a surrogate for treatment with a highly selective and efficient PKCη inhibitor. Collectively, our data suggest that targeting the CTLA4-PKCη-GIT-PAK-PIX signaling pathway in Tregs could represent a novel immunotherapeutic strategy to alleviate the negative impact of Tregs on antitumor immune responses. Citation Format: Christophe Pedros, Hsin-Yu Liu, Ann J. Canonigo-Balancio, Kok-Fai Kong, Amnon Altman. Requirement of Treg-intrinsic CTLA4-PKCeta signaling pathway for suppressing tumor immunity [abstract]. In: Proceedings of the Fourth CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; Sept 30-Oct 3, 2018; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2019;7(2 Suppl):Abstract nr A211.