Identification of CD112R as a new coinhibitory receptor for CD112

Abstract

Abstract Cancer immunotherapy has had great success in the clinical setting, with immunomodulating agents targeting immune checkpoints (including CTLA-4 and PD-1) leading the way. However, the overall response rate is still low and its effectiveness on certain tumors is disappointing. Therefore, identifying novel T cell checkpoints is critically needed, for new treatment strategies. TIGIT and CD226 emerge as a novel T cell cosignaling pathway with the potential of cancer immunotherapy. CD226 and TIGIT serve as a costimulatory receptor or a coinhibitory receptor respectively for the ligand CD155 (PVR) and CD112 (PVRL2). In this study, we identified CD112R as a missing coreceptor of this important PVR-like network. CD112R, also a member of the PVR family, is preferentially expressed on T cells and inhibits TCR-mediated signal. We further identified that CD112, widely expressed on antigen-presenting cells and tumor cells, is the ligand for CD112R with high affinity. CD112R competes with CD226 to bind CD112. Disrupting the CD112R/CD112 interaction enhances human T-cell response. Thus, our studies identify CD112R as a novel checkpoint for human T cell, and modulating this pathway will offer new targets for future immunotherapy.