程序性细胞死亡蛋白 1 (PD-1) 是 T 细胞表面表达的免疫检查点受体。 PD-1的高表达导致肿瘤微环境（TME）中的T细胞功能障碍。然而，PD-1的细胞内运输和质膜呈递机制仍不清楚。综合分析多个肺癌患者数据库，筛选Rab蛋白和潜在的免疫相关信号通路。在 Jurkat T 细胞、脾细胞和人外周血单核细胞 (PBMC) 中进行成像和各种生化测定。 Rab37 基因敲除小鼠和肺癌患者标本被用来验证这一概念。在这里，我们确定了 Rab37 小 GTP 酶介导的 PD-1 细胞内运输和质膜呈递的新机制，以维持 T 细胞耗竭，从而导致患者预后不佳。 PD-1 以 GTP 依赖性方式与 T 细胞的 Rab37 特异性囊泡共定位，由此 Rab37 介导 PD-1 的动态运输和膜呈递。然而，糖基化突变体 PD-1 延迟了 Rab37 囊泡的货物招募，从而阻碍了膜的呈递。值得注意的是，与野生型相比，荷瘤 Rab37 敲除小鼠的肿瘤浸润 T 细胞的 T 细胞增殖和活性上调。临床上，多重免疫荧光-免疫组化检测表明，具有高 Rab37 /PD-1 /TIM3 /CD8 肿瘤浸润 T 细胞谱的患者与晚期肿瘤分期和较差的总生存期相关。此外，来自患者的人类 PBMC 表现出 Rab37 高表达，这与 CD8 T 细胞中 PD-1 和 TIM3 水平升高呈正相关，从而降低了杀肿瘤活性。我们的结果提供了第一个证据，表明 Rab37 小 GTP 酶介导 PD 的运输和膜呈递-1维持T细胞耗竭，以及肺癌TME T细胞中Rab37/PD-1轴的促肿瘤功能。肿瘤浸润 CD8 T 细胞中 Rab37high/PD-1high/TIM3high 的表达谱是肺癌患者预后不良的生物标志物。© 2024。作者。

Programmed cell death protein 1 (PD-1) is an immune checkpoint receptor expressed on the surface of T cells. High expression of PD-1 leads to T-cell dysfunction in the tumor microenvironment (TME). However, the mechanism of intracellular trafficking and plasma membrane presentation of PD-1 remains unclear.Multiple databases of lung cancer patients were integratively analyzed to screen Rab proteins and potential immune-related signaling pathways. Imaging and various biochemical assays were performed in Jurkat T cells, splenocytes, and human peripheral blood mononuclear cells (PBMCs). Rab37 knockout mice and specimens of lung cancer patients were used to validate the concept.Here, we identify novel mechanisms of intracellular trafficking and plasma membrane presentation of PD-1 mediated by Rab37 small GTPase to sustain T cell exhaustion, thereby leading to poor patient outcome. PD-1 colocalized with Rab37-specific vesicles of T cells in a GTP-dependent manner whereby Rab37 mediated dynamic trafficking and membrane presentation of PD-1. However, glycosylation mutant PD-1 delayed cargo recruitment to the Rab37 vesicles, thus stalling membrane presentation. Notably, T cell proliferation and activity were upregulated in tumor-infiltrating T cells from the tumor-bearing Rab37 knockout mice compared to those from wild type. Clinically, the multiplex immunofluorescence-immunohistochemical assay indicated that patients with high Rab37+/PD-1+/TIM3+/CD8+ tumor infiltrating T cell profile correlated with advanced tumor stages and poor overall survival. Moreover, human PBMCs from patients demonstrated high expression of Rab37, which positively correlated with elevated levels of PD-1+ and TIM3+ in CD8+ T cells exhibiting reduced tumoricidal activity.Our results provide the first evidence that Rab37 small GTPase mediates trafficking and membrane presentation of PD-1 to sustain T cell exhaustion, and the tumor promoting function of Rab37/PD-1 axis in T cells of TME in lung cancer. The expression profile of Rab37high/PD-1high/TIM3high in tumor-infiltrating CD8+ T cells is a biomarker for poor prognosis in lung cancer patients.© 2024. The Author(s).