Lactate increases stemness of CD8 + T cells to augment anti-tumor immunity.
Lactate increases stemness of CD8 + T cells to augment anti-tumor immunity.
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DOI：
10.1038/s41467-022-32521-8
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发表时间：
2022-09-06
影响因子：
16.6
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中科院分区：
文献类型：
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乳酸是葡萄糖分子糖酵解代谢产生的关键代谢物，也是许多细胞类型的主要碳燃料来源。在肿瘤免疫微环境中，乳酸对癌症和免疫细胞的影响可能非常复杂且难以破译，这进一步被糖酵解的副产物酸性质子所混淆。本研究表明，乳酸能够增加CD8+ T细胞的干性，增强抗肿瘤免疫。皮下注射乳酸钠而非葡萄糖对移植MC38肿瘤小鼠产生CD8+ T细胞依赖性肿瘤生长抑制作用。单细胞转录组学分析显示，肿瘤内CD3+细胞中表达CD8+ T细胞的干细胞样tcf -1的比例增加，这一表型通过体外乳酸处理T细胞证实。从机制上讲，乳酸抑制组蛋白去乙酰化酶活性，导致Tcf7超级增强子位点H3K27乙酰化增加，导致Tcf7基因表达增加。体外乳酸预处理的CD8+ T细胞在过继转移到荷瘤小鼠后有效抑制肿瘤生长。我们的研究结果证明了乳酸在抗肿瘤免疫中的内在作用不依赖于乳酸的ph依赖性，并可能促进癌症免疫治疗。癌细胞糖酵解代谢产生的乳酸与免疫抑制功能有关。本文作者表明，当乳酸远离酸性质子时，可以抑制CD8 + T细胞中的组蛋白去乙酰化酶，从而使它们变成有效的抗肿瘤免疫细胞。
Lactate is a key metabolite produced from glycolytic metabolism of glucose molecules, yet it also serves as a primary carbon fuel source for many cell types. In the tumor-immune microenvironment, effect of lactate on cancer and immune cells can be highly complex and hard to decipher, which is further confounded by acidic protons, a co-product of glycolysis. Here we show that lactate is able to increase stemness of CD8+ T cells and augments anti-tumor immunity. Subcutaneous administration of sodium lactate but not glucose to mice bearing transplanted MC38 tumors results in CD8+ T cell-dependent tumor growth inhibition. Single cell transcriptomics analysis reveals increased proportion of stem-like TCF-1-expressing CD8+ T cells among intra-tumoral CD3+ cells, a phenotype validated by in vitro lactate treatment of T cells. Mechanistically, lactate inhibits histone deacetylase activity, which results in increased acetylation at H3K27 of the Tcf7 super enhancer locus, leading to increased Tcf7 gene expression. CD8+ T cells in vitro pre-treated with lactate efficiently inhibit tumor growth upon adoptive transfer to tumor-bearing mice. Our results provide evidence for an intrinsic role of lactate in anti-tumor immunity independent of the pH-dependent effect of lactic acid, and might advance cancer immune therapy. Lactic acid from glycolytic metabolism of cancer cells has been associated with immune suppressive functions. Here authors show that lactate, when depart from the acidic protons, inhibits histone deacetylases in CD8 + T cells, which turns them into potent anti-tumour immune cells.
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影响因子：
38.3
作者：
Luo M;Wang H;Wang Z;Cai H;Lu Z;Li Y;Du M;Huang G;Wang C;Chen X;Porembka MR;Lea J;Frankel AE;Fu YX;Chen ZJ;Gao J
通讯作者：
Gao J
影响因子：
32.4
作者：
He B;Xing S;Chen C;Gao P;Teng L;Shan Q;Gullicksrud JA;Martin MD;Yu S;Harty JT;Badovinac VP;Tan K;Xue HH
通讯作者：
Xue HH
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：
64.5
作者：
Chang CH;Curtis JD;Maggi LB Jr;Faubert B;Villarino AV;O'Sullivan D;Huang SC;van der Windt GJ;Blagih J;Qiu J;Weber JD;Pearce EJ;Jones RG;Pearce EL
通讯作者：
Pearce EL
影响因子：
64.5
作者：
Johnson MO;Wolf MM;Madden MZ;Andrejeva G;Sugiura A;Contreras DC;Maseda D;Liberti MV;Paz K;Kishton RJ;Johnson ME;de Cubas AA;Wu P;Li G;Zhang Y;Newcomb DC;Wells AD;Restifo NP;Rathmell WK;Locasale JW;Davila ML;Blazar BR;Rathmell JC
通讯作者：
Rathmell JC