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

Autor: Ma J; Department of Immunology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China., Tang L; Department of Immunology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China., Tan Y; Department of Biochemistry & Molecular Biology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China., Xiao J; Department of Immunology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China., Wei K; Department of Immunology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China., Zhang X; Department of Immunology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China., Ma Y; Department of Biochemistry & Molecular Biology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China., Tong S; Department of Immunology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China., Chen J; Department of Immunology & National Key Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China., Zhou N; Department of Immunology & National Key Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China., Yang L; Biotherapy Center and Cancer Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China., Lei Z; Department of Oncology, The Central Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China., Li Y; Hubei Provincial Key Laboratory for Applied Toxicology, Hubei Provincial Center for Disease Control and Prevention, Wuhan, China., Lv J; Department of Immunology & National Key Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China., Liu J; Cardiovascular Surgery, Union Hospital, Huazhong University of Science and Technology, Wuhan, China., Zhang H; Department of Pathology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China., Tang K; Department of Biochemistry & Molecular Biology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China., Zhang Y; Biotherapy Center and Cancer Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China., Huang B; Department of Biochemistry & Molecular Biology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China. tjhuangbo@hotmail.com.; Department of Immunology & National Key Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China. tjhuangbo@hotmail.com.
Jazyk: angličtina
Zdroj: Nature immunology [Nat Immunol] 2024 Mar; Vol. 25 (3), pp. 552-561. Date of Electronic Publication: 2024 Jan 23.
DOI: 10.1038/s41590-023-01738-0
Abstrakt: 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.
(© 2024. The Author(s).)
Databáze: MEDLINE
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