Rab37 mediates trafficking and membrane presentation of PD-1 to sustain T cell exhaustion in lung cancer.

IF 9 2区 医学 Q1 CELL BIOLOGY Journal of Biomedical Science Pub Date : 2024-02-07 DOI:10.1186/s12929-024-01009-6
Wan-Ting Kuo, I-Ying Kuo, Hung-Chia Hsieh, Ssu-Ting Wu, Wu-Chou Su, Yi-Ching Wang
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Abstract

Background: 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.

Methods: 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.

Results: 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.

Conclusions: 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.

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Rab37介导PD-1的贩运和膜呈现,以维持肺癌中T细胞的衰竭。
背景程序性细胞死亡蛋白 1(PD-1)是一种表达在 T 细胞表面的免疫检查点受体。PD-1 的高表达会导致肿瘤微环境(TME)中的 T 细胞功能障碍。然而,PD-1的胞内转运和质膜表达机制仍不清楚:方法:综合分析肺癌患者的多个数据库,筛选Rab蛋白和潜在的免疫相关信号通路。在 Jurkat T 细胞、脾脏细胞和人类外周血单核细胞(PBMCs)中进行了成像和各种生化检测。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,我们发现了由 Rab37 小 GTPase 介导的 PD-1 细胞内转运和质膜呈现的新机制,这种机制可维持 T 细胞衰竭,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,Rab37介导了PD-1的动态贩运和膜呈现。然而,糖基化突变的PD-1会延迟货物招募到Rab37小泡,从而阻碍膜呈现。值得注意的是,与野生型小鼠相比,Rab37基因敲除小鼠肿瘤浸润T细胞的增殖和活性都有所提高。临床上,多重免疫荧光-免疫组化分析表明,Rab37+/PD-1+/TIM3+/CD8+肿瘤浸润T细胞高的患者与肿瘤晚期和总生存率低有关。此外,患者的人 PBMCs 表现出 Rab37 的高表达,这与 CD8+ T 细胞中 PD-1+ 和 TIM3+ 水平的升高呈正相关,表现出杀瘤活性降低:我们的研究结果首次证明了Rab37小GTP酶介导了PD-1的贩运和膜呈递以维持T细胞衰竭,以及Rab37/PD-1轴在肺癌TME的T细胞中的肿瘤促进功能。肿瘤浸润CD8+ T细胞中Rab37高/PD-1高/TIM3高的表达谱是肺癌患者预后不良的生物标志物。
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来源期刊
Journal of Biomedical Science
Journal of Biomedical Science 医学-医学:研究与实验
CiteScore
18.50
自引率
0.90%
发文量
95
审稿时长
1 months
期刊介绍: The Journal of Biomedical Science is an open access, peer-reviewed journal that focuses on fundamental and molecular aspects of basic medical sciences. It emphasizes molecular studies of biomedical problems and mechanisms. The National Science and Technology Council (NSTC), Taiwan supports the journal and covers the publication costs for accepted articles. The journal aims to provide an international platform for interdisciplinary discussions and contribute to the advancement of medicine. It benefits both readers and authors by accelerating the dissemination of research information and providing maximum access to scholarly communication. All articles published in the Journal of Biomedical Science are included in various databases such as Biological Abstracts, BIOSIS, CABI, CAS, Citebase, Current contents, DOAJ, Embase, EmBiology, and Global Health, among others.
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