Yin Shenhui, Li Chunzhen, Shen Xin, Yu Guanyu, Cui Likun, Wu Yunyang, He Yixian, Yu Shu, Chen Jie, Lu Shaoteng, Qiu Guifang, Song Mengqi, Qian Cheng, Zou Zui, Yu Yizhi, Xu Sheng
National Key Laboratory of Immunity & Inflammation, Naval Medical University/Second Military Medical University, Shanghai, 200433, China.
Department of Colorectal Surgery, Changhai Hospital, Naval Medical University, Shanghai, 200433, China.
Adv Sci (Weinh). 2024 Dec;11(45):e2403438. doi: 10.1002/advs.202403438. Epub 2024 Oct 7.
CD8 T cells play a critical role in cancer immune-surveillance and pathogen elimination. However, their effector function can be severely impaired by inhibitory receptors such as programmed death-1 (PD-1) and T cell immunoglobulin domain and mucin domain-3 (Tim-3). Here Siglec-G is identified as a coinhibitory receptor that limits CD8 T cell function. Siglec-G is highly expressed on tumor-infiltrating T cells and is enriched in the exhausted T cell subset. Ablation of Siglec-G enhances the efficacy of adoptively transferred T cells and chimeric antigen receptor (CAR) T cells in suppressing solid tumors growth. Mechanistically, sialoglycan ligands, such as CD24 on tumor cells, activate the Siglec-G-SHP2 axis in CD8 T cells, impairing metabolic reprogramming from oxidative phosphorylation to glycolysis, which dampens cytotoxic T lymphocyte (CTL) activation, expansion, and cytotoxicity. These findings discover a critical role for Siglec-G in inhibiting CD8 T cell responses, suggesting its potential therapeutic effect in adoptive T cell therapy and tumor immunotherapy.
CD8 T细胞在癌症免疫监视和病原体清除中发挥着关键作用。然而，它们的效应功能可能会受到诸如程序性死亡-1（PD-1）和T细胞免疫球蛋白结构域和粘蛋白结构域-3（Tim-3）等抑制性受体的严重损害。在此，唾液酸结合免疫球蛋白样凝集素-G（Siglec-G）被鉴定为一种限制CD8 T细胞功能的共抑制受体。Siglec-G在肿瘤浸润性T细胞上高度表达，并在耗竭的T细胞亚群中富集。敲除Siglec-G可增强过继转移T细胞和嵌合抗原受体（CAR）T细胞抑制实体瘤生长的功效。从机制上讲，肿瘤细胞上的唾液酸糖配体，如CD24，激活CD8 T细胞中的Siglec-G-SHP2轴，损害从氧化磷酸化到糖酵解的代谢重编程，从而抑制细胞毒性T淋巴细胞（CTL）的激活、扩增和细胞毒性。这些发现揭示了Siglec-G在抑制CD8 T细胞反应中的关键作用，表明其在过继性T细胞疗法和肿瘤免疫疗法中的潜在治疗作用。
