Rgs16 promotes antitumor CD8+ T cell exhaustion.

T cells become functionally exhausted in tumors, limiting T cell–based immunotherapies. Although several transcription factors regulating the exhausted T (T_ex) cell differentiation are known, comparatively little is known about the regulators of T_ex cell survival. Here, we reported that the regulator of G protein signaling 16 (Rgs-16) suppressed T_ex cell 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. Rgs16 deficiency inhibited CD8⁺ T cell apoptosis and promoted antitumor effector functions of CD8⁺ T cells. Furthermore, Rgs16 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. Rgs16 deficiency enhanced antitumor CD8⁺ TIL survival in an Erk1-dependent manner. Loss of function of Erk1 decreased antitumor functions of Rgs16-deficient CD8⁺ T cells. RGS16 mRNA expression levels in CD8⁺ TILs of patients with melanoma negatively correlated with genes associated with T cell stemness, such as SELL, TCF7, and IL7R, and predicted low responses to PD-1 blockade. This study uncovers Rgs16 as an inhibitor of T_ex cell survival in tumors and has implications for improving T cell–based immunotherapies. Rgs16 is exhausting: Many cancer therapies are limited by T cell exhaustion; thus, understanding the mechanisms by which T cells become exhausted in tumors is crucial for improving cancer therapies. Weisshaar et al. found that Rgs16, a regulator of G protein signaling, was linked to CD8⁺ T cell dysfunction and death in an Erk1-mediated manner in melanoma tumors. Knocking out Rgs16 rescued CD8⁺ T cell functionality and survival in tumors, leading to slower tumor growth and improving the efficacy of immune checkpoint blockade. Last, Rgs16 correlated to exhausted T cells and predicted poor responses to PD-1 blockade in patients with melanoma. Thus, Rgs16 regulates CD8⁺ T cell function in tumors and is a potential target to improve cancer therapies. [ABSTRACT FROM AUTHOR]