肿瘤细胞治疗研究
英文原题：Tumor-specific but immunosuppressive CD39(+)CD8(+) T cells exhibit double-faceted roles in clear cell renal cell carcinoma.
Tumor-specific but immunosuppressive CD39(+)CD8(+) T cells exhibit double-faceted roles in clear cell renal cell carcinoma.
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CD39 + CD8 + T 细胞被认为是 CD8 + TIL（肿瘤浸润淋巴细胞）（TILs）中的肿瘤抗原特异性细胞。
CD39+ CD8+ T细胞是CD8+TIL（肿瘤浸润淋巴细胞）中的肿瘤抗原特异性细胞。然而，据报道，缺氧肿瘤模型中的CD39+ CD8+ T细胞也具有免疫抑制活性。在此，我们研究透明细胞肾细胞癌（ccRCC）中的CD39+ CD8+ TIL；ccRCC是一种与Von Hippel-Lindau（VHL）突变相关的缺氧肿瘤。单细胞分析证实，CD39+ CD8+细胞是肿瘤特异性CD8+ TIL中的终末耗竭亚群。cAMP和T细胞受体（TCR）信号可直接诱导CD39+ CD8+ T细胞发育。对肾细胞癌（RCC）队列分析发现，CD39+ CD8+ TIL比例与肿瘤突变负荷高及缺氧特征相关。离体功能实验显示，CD39+ CD8+ TIL通过外核苷酸酶活性和腺苷依赖机制发挥免疫抑制作用。ccRCC患者中CD39+ CD8+ TIL富集提示预后较差，但也可预测患者对抗程序性细胞死亡蛋白1（PD-1）治疗有较好应答。CD39+ CD8+ TIL兼具肿瘤抗原特异性和免疫抑制活性这两种特性，解释了其在ccRCC中看似矛盾的预后意义。
CD39 + CD8 + T cells are known as tumor-antigen-specific cells among CD8 + tumor-infiltrating lymphocytes (TILs). However, CD39 + CD8 + T cells also reportedly exhibit immunosuppressive activity in hypoxic tumor models. Here, we investigate CD39 + CD8 + TILs in clear cell renal cell carcinoma (ccRCC), a Von Hippel-Lindau (VHL) mutation-associated hypoxic tumor. Single-cell analyses confirm that CD39 + CD8 + cells are a terminally exhausted subset of tumor-specific CD8 + TILs. CD39 + CD8 + T cell development is directly induced by cAMP and T cell receptor (TCR) signaling. Analysis of a renal cell carcinoma (RCC) cohort reveals that the proportion of CD39 + CD8 + TILs is associated with a high tumor mutational burden and hypoxic features. Ex vivo functional assays reveal that CD39 + CD8 + TILs exert immunosuppressive activity via ectonucleotidase activity- and adenosine-dependent mechanisms. CD39 + CD8 + TIL enrichment predicts poor prognosis in patients with ccRCC yet also predicts favorable treatment responses to anti-programmed cell death protein 1 (PD-1) therapy. This paradoxical prognostic significance in ccRCC is explained by the dual properties of CD39 + CD8 + TILs: tumor antigen specificity and immunosuppressive activity.
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