Hao Chi, Shouyan Deng, Ke Xu, Yibo Zhang, Teng Song, Jianghong Yu, Yiting Wang, Jiayang Liu, Yuan Zhang, Jiawei Shi, Yungang Wang, Jie Xu
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引用次数: 0
摘要
肿瘤微环境中的 T 细胞经常表现出功能失调的特征,从而影响其激发先天性免疫反应和治疗诱导性免疫反应的能力。免疫功能失调的调节因子是激活抗肿瘤免疫的治疗靶点。在这项研究中,我们发现半隐形蛋白3G(SEMA3G)是癌症免疫反应的关键调节因子。SEMA3G在多种人类癌症中广泛上调,其表达与肿瘤进展呈正相关。SEMA3G是一种配体,可抑制T细胞的活化和功能。一种全面的受体筛选方法表明,与 NRP2 相比,SEMA3G 对神经蛋白 NRP1 的亲和力明显更强。此外,SEMA3G 主要通过 NRP1 阻碍 T 细胞的功能。利用CRISPR/Cas9技术破坏SEMA3G或用中和抗体阻断SEMA3G,可有效恢复CD8+ T细胞的细胞毒性并抑制体内肿瘤的生长。这项研究强调了SEMA3G在肿瘤内T细胞功能障碍中的作用,并提出了以SEMA3G为靶点的癌症免疫治疗策略。
SEMA3G-NRP1 Signaling Functions as an Immune Checkpoint that Enables Tumor Immune Evasion by Impairing T Cell Cytotoxicity
T cells within the tumor microenvironment frequently exhibit dysfunctional characteristics that compromise their ability to elicit both innate and therapeutic-induced immune responses. Regulators of immune dysfunction represent therapeutic targets to activate anti-tumor immunity. In this study, we identified semaphorin 3G (SEMA3G) as a key regulator of immune responses in cancer. SEMA3G was widely upregulated in diverse human cancers, and its expression was positively correlated with tumor progression. SEMA3G acted as a ligand that inhibited the activation and functionality of T cells. A comprehensive receptor screening approach demonstrated that SEMA3G exhibited a significantly stronger affinity for neuropilin NRP1 compared to NRP2. Furthermore, SEMA3G primarily impeded T-cell functions via NRP1. Disruption of SEMA3G using CRISPR/Cas9 technology or blockade with a neutralizing antibody effectively restored the cytotoxicity of CD8+ T cells and inhibited the growth of tumors in vivo. This research underscores the role of SEMA3G in T-cell dysfunction within tumors and proposes a targeting SEMA3G as a cancer immunotherapeutic strategy.
期刊介绍:
Cancer Research, published by the American Association for Cancer Research (AACR), is a journal that focuses on impactful original studies, reviews, and opinion pieces relevant to the broad cancer research community. Manuscripts that present conceptual or technological advances leading to insights into cancer biology are particularly sought after. The journal also places emphasis on convergence science, which involves bridging multiple distinct areas of cancer research.
With primary subsections including Cancer Biology, Cancer Immunology, Cancer Metabolism and Molecular Mechanisms, Translational Cancer Biology, Cancer Landscapes, and Convergence Science, Cancer Research has a comprehensive scope. It is published twice a month and has one volume per year, with a print ISSN of 0008-5472 and an online ISSN of 1538-7445.
Cancer Research is abstracted and/or indexed in various databases and platforms, including BIOSIS Previews (R) Database, MEDLINE, Current Contents/Life Sciences, Current Contents/Clinical Medicine, Science Citation Index, Scopus, and Web of Science.