Lactic acid promotes PD-1 expression in regulatory T cells in highly glycolytic tumor microenvironments
Lactic acid promotes PD-1 expression in regulatory T cells in highly glycolytic tumor microenvironments
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DOI：
10.1016/j.ccell.2022.01.001
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发表时间：
2022-02-14
期刊：
影响因子：
50.3
通讯作者：
Nishikawa, Hiroyoshi
中科院分区：
文献类型：
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作者：
Kumagai, Shogo;Koyama, Shohei;Nishikawa, Hiroyoshi
肿瘤微环境（TME）中表达程序性死亡-1（PD-1）的CD 8（+）T细胞和调节性T（Treg）细胞的平衡通过其再活化的竞争决定了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，我们发现Treg细胞在高度糖酵解的肿瘤中获得比效应T细胞更高的PD-1表达，包括MYC扩增的肿瘤和肝脏肿瘤。在低葡萄糖环境下，通过肿瘤细胞消耗葡萄糖，Treg细胞通过单羧酸转运蛋白1（MCT 1）主动吸收乳酸（LA），促进NFAT 1转运到细胞核中，从而增强PD-1的表达，而效应T细胞的PD-1表达受到抑制。PD-1阻断使表达PD-1的Treg细胞增殖，导致治疗失败。我们提出，在高度糖酵解的TME中的LA是通过上调PD-1表达的TME中Treg细胞功能的活性检查点。
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 trans location 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.