T cells become functionally exhausted in tumors, limiting T cell-based immunotherapies. Although several transcription factors regulating the exhausted T (T) cell differentiation are known, comparatively little is known about the regulators of T cell survival. Here, we reported that the regulator of G protein signaling 16 (Rgs-16) suppressed T cell survival in tumors. By performing lineage tracing using reporter mice in which mCherry marked Rgs16-expressing cells, we identified that Rgs16CD8 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. deficiency inhibited CD8... More
T cells become functionally exhausted in tumors, limiting T cell-based immunotherapies. Although several transcription factors regulating the exhausted T (T) cell differentiation are known, comparatively little is known about the regulators of T cell survival. Here, we reported that the regulator of G protein signaling 16 (Rgs-16) suppressed T cell survival in tumors. By performing lineage tracing using reporter mice in which mCherry marked Rgs16-expressing cells, we identified that Rgs16CD8 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. deficiency inhibited CD8 T cell apoptosis and promoted antitumor effector functions of CD8 T cells. Furthermore, deficiency 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. deficiency enhanced antitumor CD8 TIL survival in an Erk1-dependent manner. Loss of function of Erk1 decreased antitumor functions of -deficient CD8 T cells. mRNA expression levels in CD8 TILs of patients with melanoma negatively correlated with genes associated with T cell stemness, such as , , and , and predicted low responses to PD-1 blockade. This study uncovers Rgs16 as an inhibitor of T cell survival in tumors and has implications for improving T cell-based immunotherapies.
