The Pellino1-PKC theta Signaling Axis Is an Essential Target for Improving Antitumor CD8(+) T-lymphocyte Function

Abstract

CD8(+)T cells play an important role in the elimination of tumors. However, the underlying mechanisms involved in eliciting and maintaining effector responses in CD8(+)T cells remain to be elucidated. Pellino1 (Peli1) is a receptor signal-responsive ubiquitin E3 ligase, which acts as a critical mediator for innate immunity. Here, we found that the risk of developing tumors was dependent on Peli1 expression. Peli1 was upregulated in CD8(+)T cells among tumor-infiltrating lymphocytes (TEL). In contrast, a deficit of Pelil enhanced the maintenance and effector function of CD8(+) TILs. The development of Peli1/-deficient CD8(+)TILs prevented T-cell cxhaustion and retained the hyperactivated states of T cells to eliminate tumors. We also found that Peli1 directly interacted with protein kinase C-theta (PKC theta), a central kinase in T-cell receptor down-stream signal transduction, but whose role in tumor immunology remains unknown. Peli1 inhibited the PKC theta pathway by lysine 48-mediated ubiquitination degradation in CD8(+)TILs. In summary, the Peli1-PKC theta signaling axis is a common inhibitory mechanism that prevents antitumorCD8(+)T-cell function, and thus targeting Peli1 may be a useful therapeutic strategy for improving cytotoxic T-cell activity.