Rgs16 promotes antitumor CD8+T cell exhaustion

Abstract

T cells become functionally exhausted in tumors, limiting T cell–based immunotherapies. Although several transcription factors regulating the exhausted T (Tex) cell differentiation are known, comparatively little is known about the regulators of Texcell survival. Here, we reported that the regulator of G protein signaling 16 (Rgs-16) suppressed Texcell survival in tumors. By performing lineage tracing using reporter mice in which mCherry marked Rgs16-expressing cells, we identified that Rgs16+CD8+tumor-infiltrating lymphocytes (TILs) were terminally differentiated, expressed low levels of T cell factor 1 (Tcf1), and underwent apoptosis as early as 6 days after the onset of Rgs16 expression.Rgs16deficiency inhibited CD8+T cell apoptosis and promoted antitumor effector functions of CD8+T cells. Furthermore,Rgs16deficiency synergized with programmed cell death protein 1 (PD-1) blockade to enhance antitumor CD8+T cell responses. Proteomics revealed that Rgs16 interacted with the scaffold protein IQGAP1, suppressed the recruitment of Ras and B-Raf, and inhibited Erk1 activation.Rgs16deficiency enhanced antitumor CD8+TIL survival in an Erk1-dependent manner. Loss of function of Erk1 decreased antitumor functions ofRgs16-deficient CD8+T cells.RGS16mRNA expression levels in CD8+TILs of patients with melanoma negatively correlated with genes associated with T cell stemness, such asSELL,TCF7, andIL7R, and predicted low responses to PD-1 blockade. This study uncovers Rgs16 as an inhibitor of Texcell survival in tumors and has implications for improving T cell–based immunotherapies.