Extracellular acidosis restricts one-carbon metabolism and preserves T cell stemness.
Extracellular acidosis restricts one-carbon metabolism and preserves T cell stemness.
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DOI：
10.1038/s42255-022-00730-6
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发表时间：
2023-02
影响因子：
20.8
通讯作者：
Li, Guideng
中科院分区：
文献类型：
--
作者：
Cheng, Hongcheng;Qiu, Yajing;Xu, Yue;Chen, Li;Ma, Kaili;Tao, Mengyuan;Frankiw, Luke;Yin, Hongli;Xie, Ermei;Pan, Xiaoli;Du, Jing;Wang, Zhe;Zhu, Wenjie;Chen, Lu;Zhang, Lianjun;Li, Guideng
肿瘤微环境中酸性代谢废物的积累会抑制肿瘤浸润淋巴细胞（TIL）的效应功能。然而，酸性环境如何影响 T 细胞代谢和分化仍不清楚。在这里，我们发现，长期暴露于酸会重新编程 T 细胞的细胞内代谢和线粒体健康，并保持 T 细胞的干性。从机制上讲，细胞外酸中毒升高会通过下调 SLC7A5 损害蛋氨酸的摄取和代谢，从而改变关键 T 细胞干性基因启动子处的 H3K27me3 沉积。这些变化促进了“类干记忆”状态的维持，并提高了小鼠体内的长期持久性和抗肿瘤功效。我们的研究结果不仅揭示了细胞外酸中毒维持 T 细胞干细胞特性的意外能力，而且加深了我们对蛋氨酸代谢如何影响 T 细胞干性的理解。研究表明，长时间接触酸可以重新编程 T 细胞胞内蛋氨酸代谢，从而保持 T 细胞干性并提高抗肿瘤功效。
The accumulation of acidic metabolic waste products within the tumor microenvironment inhibits effector functions of tumor-infiltrating lymphocytes (TILs). However, it remains unclear how an acidic environment affects T cell metabolism and differentiation. Here we show that prolonged exposure to acid reprograms T cell intracellular metabolism and mitochondrial fitness and preserves T cell stemness. Mechanistically, elevated extracellular acidosis impairs methionine uptake and metabolism via downregulation of SLC7A5, therefore altering H3K27me3 deposition at the promoters of key T cell stemness genes. These changes promote the maintenance of a ‘stem-like memory’ state and improve long-term in vivo persistence and anti-tumor efficacy in mice. Our findings not only reveal an unexpected capacity of extracellular acidosis to maintain the stem-like properties of T cells, but also advance our understanding of how methionine metabolism affects T cell stemness. Prolonged exposure to acid is shown to reprogram T cell intracellular methionine metabolism to preserve T cell stemness and increase anti-tumor efficacy.
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影响因子：
64.5
作者：
Burger ML;Cruz AM;Crossland GE;Gaglia G;Ritch CC;Blatt SE;Bhutkar A;Canner D;Kienka T;Tavana SZ;Barandiaran AL;Garmilla A;Schenkel JM;Hillman M;de Los Rios Kobara I;Li A;Jaeger AM;Hwang WL;Westcott PMK;Manos MP;Holovatska MM;Hodi FS;Regev A;Santagata S;Jacks T
通讯作者：
Jacks T
影响因子：
30.5
作者：
Galletti G;De Simone G;Mazza EMC;Puccio S;Mezzanotte C;Bi TM;Davydov AN;Metsger M;Scamardella E;Alvisi G;De Paoli F;Zanon V;Scarpa A;Camisa B;Colombo FS;Anselmo A;Peano C;Polletti S;Mavilio D;Gattinoni L;Boi SK;Youngblood BA;Jones RE;Baird DM;Gostick E;Llewellyn-Lacey S;Ladell K;Price DA;Chudakov DM;Newell EW;Casucci M;Lugli E
通讯作者：
Lugli E
影响因子：
30.5
作者：
Guo Y;Xie YQ;Gao M;Zhao Y;Franco F;Wenes M;Siddiqui I;Bevilacqua A;Wang H;Yang H;Feng B;Xie X;Sabatel CM;Tschumi B;Chaiboonchoe A;Wang Y;Li W;Xiao W;Held W;Romero P;Ho PC;Tang L
通讯作者：
Tang L
影响因子：
64.8
作者：
Im SJ;Hashimoto M;Gerner MY;Lee J;Kissick HT;Burger MC;Shan Q;Hale JS;Lee J;Nasti TH;Sharpe AH;Freeman GJ;Germain RN;Nakaya HI;Xue HH;Ahmed R
通讯作者：
Ahmed R
影响因子：
82.9
作者：
Gattinoni L;Speiser DE;Lichterfeld M;Bonini C
通讯作者：
Bonini C