Transgelin 2 guards T cell lipid metabolic programming and anti-tumor function

Mounting effective immunity against pathogens and tumors relies on the successful metabolic programming of T cells by extracellular fatty acids . During this process, fatty-acid-binding protein 5 (FABP5) imports lipids that fuel mitochondrial respiration and sustain the bioenergetic requirements of...

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Main Authors Hwang, Sung-Min, Awasthi, Deepika, Jeong, Jieun, Sandoval, Tito A, Chae, Chang-Suk, Ramos, Yusibeska, Tan, Chen, Falco, Matías Marin, McBain, Ian T, Mishra, Bikash, Ivashkiv, Lionel B, Zamarin, Dmitriy, Cantillo, Evelyn, Chapman-Davis, Eloise, Holcomb, Kevin, Morales, Diana K, Rodriguez, Paulo C, Conejo-Garcia, Jose R, Kaczocha, Martin, Vähärautio, Anna, Song, Minkyung, Cubillos-Ruiz, Juan R
Format Journal Article
LanguageEnglish
Published United States 14.12.2023
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Summary:Mounting effective immunity against pathogens and tumors relies on the successful metabolic programming of T cells by extracellular fatty acids . During this process, fatty-acid-binding protein 5 (FABP5) imports lipids that fuel mitochondrial respiration and sustain the bioenergetic requirements of protective CD8 T cells . Importantly, however, the mechanisms governing this crucial immunometabolic axis remain unexplored. Here we report that the cytoskeletal organizer Transgelin 2 (TAGLN2) is necessary for optimal CD8 T cell fatty acid uptake, mitochondrial respiration, and anti-cancer function. We found that TAGLN2 interacts with FABP5, enabling the surface localization of this lipid importer on activated CD8 T cells. Analysis of ovarian cancer specimens revealed that endoplasmic reticulum (ER) stress responses elicited by the tumor microenvironment repress TAGLN2 in infiltrating CD8 T cells, enforcing their dysfunctional state. Restoring TAGLN2 expression in ER-stressed CD8 T cells bolstered their lipid uptake, mitochondrial respiration, and cytotoxic capacity. Accordingly, chimeric antigen receptor T cells overexpressing TAGLN2 bypassed the detrimental effects of tumor-induced ER stress and demonstrated superior therapeutic efficacy in mice with metastatic ovarian cancer. Our study unveils the role of cytoskeletal TAGLN2 in T cell lipid metabolism and highlights the potential to enhance cellular immunotherapy in solid malignancies by preserving the TAGLN2-FABP5 axis.