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碳酸锂通过将乳酸分流到线粒体中来激活肿瘤反应性 CD8 T 细胞。

Lithium carbonate revitalizes tumor-reactive CD8 T cells by shunting lactic acid into mitochondria.

机构信息

Department of Immunology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.

Department of Biochemistry & Molecular Biology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.

出版信息

Nat Immunol. 2024 Mar;25(3):552-561. doi: 10.1038/s41590-023-01738-0. Epub 2024 Jan 23.

DOI:10.1038/s41590-023-01738-0
PMID:38263463
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC10907288/
Abstract

The steady flow of lactic acid (LA) from tumor cells to the extracellular space via the monocarboxylate transporter symport system suppresses antitumor T cell immunity. However, LA is a natural energy metabolite that can be oxidized in the mitochondria and could potentially stimulate T cells. Here we show that the lactate-lowering mood stabilizer lithium carbonate (LC) can inhibit LA-mediated CD8 T cell immunosuppression. Cytoplasmic LA increased the pumping of protons into lysosomes. LC interfered with vacuolar ATPase to block lysosomal acidification and rescue lysosomal diacylglycerol-PKCθ signaling to facilitate monocarboxylate transporter 1 localization to mitochondrial membranes, thus transporting LA into the mitochondria as an energy source for CD8 T cells. These findings indicate that targeting LA metabolism using LC could support cancer immunotherapy.

摘要

乳酸（LA）通过单羧酸转运体协同转运系统从肿瘤细胞稳定地流向细胞外间隙，抑制抗肿瘤 T 细胞免疫。然而，LA 是一种天然的能量代谢物，可以在线粒体中被氧化，并且可能刺激 T 细胞。在这里，我们表明，降低乳酸的心境稳定剂碳酸锂（LC）可以抑制 LA 介导的 CD8 T 细胞免疫抑制。细胞质中的 LA 增加了质子向溶酶体的泵入。LC 干扰液泡型 ATP 酶以阻断溶酶体酸化并挽救溶酶体二酰基甘油-PKCθ 信号，从而促进单羧酸转运蛋白 1 定位于线粒体膜，从而将 LA 作为 CD8 T 细胞的能量来源转运到线粒体中。这些发现表明，使用 LC 靶向 LA 代谢可以支持癌症免疫治疗。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f930/10907288/6954f56c6b99/41590_2023_1738_Fig15_ESM.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f930/10907288/6954f56c6b99/41590_2023_1738_Fig15_ESM.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f930/10907288/a099151a2cbe/41590_2023_1738_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f930/10907288/8efbcba8db5e/41590_2023_1738_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f930/10907288/97ea232f0167/41590_2023_1738_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f930/10907288/a00ba87ed0f0/41590_2023_1738_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f930/10907288/50524d0a586e/41590_2023_1738_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f930/10907288/55de44dedc7d/41590_2023_1738_Fig6_ESM.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f930/10907288/1f80566aebed/41590_2023_1738_Fig7_ESM.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f930/10907288/94de3131ec13/41590_2023_1738_Fig8_ESM.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f930/10907288/f7041cc29df0/41590_2023_1738_Fig9_ESM.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f930/10907288/f511421eba49/41590_2023_1738_Fig10_ESM.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f930/10907288/a350bb4bc1de/41590_2023_1738_Fig11_ESM.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f930/10907288/373504a5b839/41590_2023_1738_Fig12_ESM.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f930/10907288/893423c588c4/41590_2023_1738_Fig13_ESM.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f930/10907288/262c911428f0/41590_2023_1738_Fig14_ESM.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f930/10907288/6954f56c6b99/41590_2023_1738_Fig15_ESM.jpg

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本文引用的文献

[1]
Carbon source availability drives nutrient utilization in CD8 T cells.

Cell Metab. 2022-9-6

[2]
PD-1 regulation by lactic acid.

Nat Cell Biol. 2022-3

[3]
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Cancer Cell. 2022-2-14

[4]
Lactic acid promotes PD-1 expression in regulatory T cells in highly glycolytic tumor microenvironments.

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Magnesium sensing via LFA-1 regulates CD8 T cell effector function.

Cell. 2022-2-17

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Acid Sphingomyelinase, a Lysosomal and Secretory Phospholipase C, Is Key for Cellular Phospholipid Catabolism.

Int J Mol Sci. 2021-8-20

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