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 (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.

Construction of a B cell-related gene pairs signature for predicting prognosis and immunotherapeutic response in non-small cell lung cancer

“…It was reported that RGS16 played central roles in immune and inflammatory responses ( 44 , 45 ). Importantly, RGS16 can inhibit the Ras-Raf-MEK-Erk signaling cascade and promotes antitumor CD8+ T cell exhaustion ( 46 ). HES1, a Notch signaling pathway target, plays both oncogenic and tumor suppressor roles in different cell types ( 47 ).…”

Reshaping the systemic tumor immune environment (STIE) and tumor immune microenvironment (TIME) to enhance immunotherapy efficacy in solid tumors

“…Most of this work is on the fate of T cell which is critical in the process of the reshaping of STIE and TIME with immunotherapy. T cell exhaustion is currently a major obstacle limiting the efficacy of T-cell-based immunotherapy [177]. The developmental hierarchy of exhausted CD8 + T cells (Tex) can be divided into four-stage according to transcriptional and epigenetic analyses, namely quiescent resident stage, proliferative circulating stage, circulating mildly cytotoxic stage, and terminally exhausted resident stage.…”

“…Although PD-1 could reinvigorate exhausted CD8 + T cells [179,181,182], this immune therapy cannot revise the exhaustion-associated epigenetic imprint [180]. Effectors like TOX, TOX2, AP-1, and RGS16 proteins play a key role in the regulation of T cell exhaustion in relation to the transcriptional and epigenetic aspects [177,[183][184][185][186]. The specific reshaping of STIE and TIME by immunotherapy is shown in Table 3, using NSCLC, HCC, and NPC as example tumors.…”

Platelet-derived TLT-1 promotes tumor progression by suppressing CD8+ T cells

“…Previously, studies on OKT3 antibody (binds to CD3ε) have demonstrated the induction of apoptosis in activated T cells or AICD ( Shi et al, 1990 ), further supporting our observations. T cell apoptosis is one of the major underlying mechanisms behind compromised antitumor immunity and consequent tumor progression ( Dong et al, 2002 ; Weisshaar et al, 2022 ). NF-κB pathway and its responsive genes have been implicated in CD3ε-induced AICD ( Huang et al, 2018 ).…”