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.

中文翻译：

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Rgs16 促进抗肿瘤 CD8 + T 细胞耗竭

T 细胞在肿瘤中功能衰竭，限制了基于 T 细胞的免疫疗法。尽管有几个转录因子调节耗尽的 T (T前任) 细胞分化是已知的，但对 T 的调节因子知之甚少前任细胞存活。在这里，我们报道了 G 蛋白信号 16 (Rgs-16) 的调节因子抑制了 T前任肿瘤中的细胞存活。通过使用 mCherry 标记 Rgs16 表达细胞的报告小鼠进行谱系追踪，我们确定了 Rgs16+CD8+肿瘤浸润淋巴细胞 (TIL) 终末分化，表达低水平的 T 细胞因子 1 (Tcf1)，并且早在 Rgs16 表达开始后 6 天就发生细胞凋亡。Rgs16缺乏抑制CD8+T细胞凋亡和促进CD8的抗肿瘤效应功能+T细胞。此外，Rgs16缺乏与程序性细胞死亡蛋白 1 (PD-1) 阻断协同作用以增强抗肿瘤 CD8+T细胞反应。蛋白质组学显示，Rgs16 与支架蛋白 IQGAP1 相互作用，抑制 Ras 和 B-Raf 的募集，并抑制 Erk1 激活。Rgs16缺乏增强抗肿瘤CD8+TIL 以依赖 Erk1 的方式存活。Erk1 的功能丧失降低了Rgs16-缺乏CD8+T细胞。RGS16CD8中的mRNA表达水平+黑色素瘤患者的 TIL 与 T 细胞干性相关基因呈负相关，例如卖,TCF7， 和IL7R，并预测对 PD-1 阻断的低反应。这项研究揭示了 Rgs16 作为 T 的抑制剂前任细胞在肿瘤中的存活，并对改善基于 T 细胞的免疫疗法具有重要意义。