Bulk RNA sequence and bulk ATAC sequence of treated murine CD8+ T cells. Bulk RNA sequence and bulk ATAC sequence of treated murine CD8+ T cells

We identify that GSH maintains the function of CD8+ T cell and GSH metabolism is interacting with A2AR signaling pathway to reshape the metabolism and anti-function in CD8+ T cell. We found A2AR signaling blockade leads to the upregulation of GSH metabolism related genes and loss of the genes abolishes the benefits from A2AR antagonist on CD8+ T cells. Considering to the essential role of GSH metabolism in ferroptosis, we combined the potent ferroptosis inhibitor liproxstatin-1 (Lip-1) and A2AR antagonist (SCH58261) to treat CD8+ T cells. Notably, our combination therapy significantly promotes the anti-tumor immunity of CD8+ T cells with delayed tumor growth in tumor bearing mice. Overall design: Examination of gene profile in CD8+ T cells from tumor bearing mice treated with or without anti-CD73; or from in vitro 7-days culture with SCH58261 (A2ARi), Lip-1 or A2ARi/Lip-1 treatment

本研究证实，谷胱甘肽（Glutathione, GSH）可维持CD8+ T细胞的功能，且谷胱甘肽代谢与腺苷A2A受体（A2AR）信号通路相互作用，重塑CD8+ T细胞的代谢状态与抗肿瘤功能。研究发现，阻断A2AR信号通路可上调谷胱甘肽代谢相关基因的表达，而敲除这些基因则会抵消A2AR拮抗剂对CD8+ T细胞的有益作用。鉴于谷胱甘肽代谢在铁死亡（ferroptosis）中的关键作用，我们联合使用强效铁死亡抑制剂脂氧他汀-1（Liproxstatin-1, Lip-1）与A2AR拮抗剂SCH58261，对CD8+ T细胞进行处理。值得注意的是，联合疗法可显著增强CD8+ T细胞的抗肿瘤免疫能力，使荷瘤小鼠的肿瘤生长得以延缓。实验整体设计：对经或未经抗CD73抗体处理的荷瘤小鼠体内分离的CD8+ T细胞进行基因表达谱分析；或对经SCH58261（A2AR拮抗剂，A2ARi）、Lip-1或二者联合处理的体外培养7天的CD8+ T细胞开展基因表达谱检测。