The balance of programmed death-1 (PD-1)-expressing CD8+ T cells and regulatory T (Treg) cells in the tumor microenvironment (TME) determines the clinical efficacy of PD-1 blockade therapy through the competition of their reactivation. However, factors that determine this balance remain unknown. Here, we show that Treg cells gain higher PD-1 expression than effector T cells in highly glycolytic tumors, including MYC-amplified tumors and liver tumors. Under low-glucose environments via glucose consumption by tumor cells, Treg cells actively absorbed lactic acid (LA) through monocarboxylate transporter 1 (MCT1), promoting NFAT1 translocation into the nucleus, thereby enhancing the expression of PD-1, whereas PD-1 expression by effector T cells was dampened. PD-1 blockade invigorated the PD-1-expressing Treg cells, resulting in treatment failure. We propose that LA in the highly glycolytic TME is an active checkpoint for the function of Treg cells in the TME via upregulation of PD-1 expression.

中文翻译：

程序性死亡-1 (PD-1)-表达 CD8 +的平衡肿瘤微环境 (TME) 中的 T 细胞和调节性 T (Treg) 细胞通过它们的再激活竞争决定了 PD-1 阻断治疗的临床疗效。然而，决定这种平衡的因素仍然未知。在这里，我们显示在高度糖酵解的肿瘤（包括 MYC 扩增的肿瘤和肝肿瘤）中，Treg 细胞比效应 T 细胞获得更高的 PD-1 表达。在肿瘤细胞消耗葡萄糖的低糖环境下，Treg 细胞通过单羧酸转运蛋白 1 (MCT1) 主动吸收乳酸 (LA)，促进 NFAT1 易位进入细胞核，从而增强 PD-1 的表达，而 PD-1 的表达效应 T 细胞被抑制。PD-1 阻断激活了表达 PD-1 的 Treg 细胞，导致治疗失败。