美国匹兹堡大学Greg M. Delgoffe团队近期取得重要工作进展，他们研究发现缺氧驱动耗竭T细胞中CD39依赖性抑制功能以限制抗肿瘤免疫。相关研究成果2022年12月21日在线发表于《自然—免疫学》杂志上。

据介绍，CD8⁺ T细胞对于癌细胞的清除至关重要。肿瘤微环境（TME）内的因素可以将这些细胞驱动到一种称为衰竭的低功能状态。最终末期耗竭T（tT_ex）细胞对检查点阻断免疫疗法具有抵抗力，反而可能限制免疫治疗的效果。

研究人员发现，肿瘤内CD8⁺ tT_ex细胞具有CD4⁺ Foxp3⁺调节性T细胞的转录特征，并且同样能够在体外直接抑制T细胞增殖。tT_ex细胞抑制需要产生免疫抑制腺苷的CD39。内源性CD8⁺ T细胞中CD39的限制性缺失导致肿瘤进展缓慢，免疫治疗反应性改善，转移的肿瘤特异性T细胞浸润增强。肿瘤缺氧诱导tT_ex细胞产生CD39，因此缺氧的缓解限制了tT_ex的抑制。

总之，这些数据表明，tT_ex细胞是癌症中的重要调节群体，限制它们的产生、重新编程它们的免疫抑制状态或将它们从TME中移除的策略可能会加强免疫治疗效果。

附：英文原文

Title: Hypoxia drives CD39-dependent suppressor function in exhausted T cells to limit antitumor immunity

Author: Vignali, Paolo D. A., DePeaux, Kristin, Watson, McLane J., Ye, Chenxian, Ford, B. Rhodes, Lontos, Konstantinos, McGaa, Nicole K., Scharping, Nicole E., Menk, Ashley V., Robson, Simon C., Poholek, Amanda C., Rivadeneira, Dayana B., Delgoffe, Greg M.

Issue&Volume: 2022-12-21

Abstract: CD8+ T cells are critical for elimination of cancer cells. Factors within the tumor microenvironment (TME) can drive these cells to a hypofunctional state known as exhaustion. The most terminally exhausted T (tTex) cells are resistant to checkpoint blockade immunotherapy and might instead limit immunotherapeutic efficacy. Here we show that intratumoral CD8+ tTex cells possess transcriptional features of CD4+Foxp3+ regulatory T cells and are similarly capable of directly suppressing T cell proliferation ex vivo. tTex cell suppression requires CD39, which generates immunosuppressive adenosine. Restricted deletion of CD39 in endogenous CD8+ T cells resulted in slowed tumor progression, improved immunotherapy responsiveness and enhanced infiltration of transferred tumor-specific T cells. CD39 is induced on tTex cells by tumor hypoxia, thus mitigation of hypoxia limits tTex suppression. Together, these data suggest tTex cells are an important regulatory population in cancer and strategies to limit their generation, reprogram their immunosuppressive state or remove them from the TME might potentiate immunotherapy.

DOI: 10.1038/s41590-022-01379-9

Source: https://www.nature.com/articles/s41590-022-01379-9