Transgelin 2 guards T cell lipid metabolism and antitumour function Journal Article
| Authors: | Hwang, S. M.; Awasthi, D.; Jeong, J.; Sandoval, T. A.; Chae, C. S.; Ramos, Y.; Tan, C.; Marin Falco, M.; Salvagno, C.; Emmanuelli, A.; McBain, I. T.; Mishra, B.; Ivashkiv, L. B.; Zamarin, D.; Cantillo, E.; Chapman-Davis, E.; Holcomb, K.; Morales, D. K.; Yu, X.; Rodriguez, P. C.; Conejo-Garcia, J. R.; Kaczocha, M.; Vähärautio, A.; Song, M.; Cubillos-Ruiz, J. R. |
| Article Title: | Transgelin 2 guards T cell lipid metabolism and antitumour function |
| Abstract: | Mounting effective immunity against pathogens and tumours relies on the successful metabolic programming of T cells by extracellular fatty acids1–3. Fatty-acid-binding protein 5 (FABP5) has a key role in this process by coordinating the efficient import and trafficking of lipids that fuel mitochondrial respiration to sustain the bioenergetic requirements of protective CD8+ T cells4,5. However, the mechanisms that govern this immunometabolic axis remain unexplored. Here we report that the cytoskeletal organizer transgelin 2 (TAGLN2) is necessary for optimal fatty acid uptake, mitochondrial respiration and anticancer function in CD8+ T cells. TAGLN2 interacts with FABP5 to facilitate its cell surface localization and function in activated CD8+ T cells. Analyses of ovarian cancer specimens revealed that endoplasmic reticulum (ER) stress responses induced by the tumour microenvironment repress TAGLN2 in infiltrating CD8+ T cells, thereby enforcing their dysfunctional state. Restoring TAGLN2 expression in ER-stressed CD8+ T cells increased their lipid uptake, mitochondrial respiration and cytotoxic capacity. Accordingly, chimeric antigen receptor T cells overexpressing TAGLN2 bypassed the detrimental effects of tumour-induced ER stress and demonstrated therapeutic efficacy in mice with metastatic ovarian cancer. Our study establishes 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. © The Author(s), under exclusive licence to Springer Nature Limited 2024. |
| Keywords: | controlled study; human tissue; unclassified drug; nonhuman; flow cytometry; ki 67 antigen; transcription factor foxp3; cd8+ t lymphocyte; t lymphocyte; cd8-positive t-lymphocytes; ovarian neoplasms; mouse; animal; cytology; metabolism; animals; mice; gene; cancer immunotherapy; ovary cancer; gene expression; confocal microscopy; lipid; animal experiment; protein; small interfering rna; antineoplastic activity; cytotoxicity; immunofluorescence; pathology; cell line, tumor; microfilament proteins; granzyme b; immunology; antigen; genetic transfection; gamma interferon; chromatin immunoprecipitation; ovary tumor; tumor cell line; western blotting; immunoprecipitation; chimeric antigen receptor; electroporation; fatty acids; actin binding protein; cxcr4 gene; immunity; tumor; drug therapy; mitochondria; fatty acid binding protein; fluorescence activated cell sorting; fatty acid; lipid metabolism; mitochondrion; bioluminescence; lipid transport; tumor microenvironment; mitochondrial respiration; rna isolation; peptides and proteins; fatty acid transport; liquid chromatography-mass spectrometry; trafficking; muscle proteins; cd36 antigen; endoplasmic reticulum stress; muscle protein; eomes gene; xbp1 gene; fluorescence intensity; cell respiration; lipidomics; cancer; humans; human; female; article; luciferase assay; coimmunoprecipitation; transgelin; receptors, chimeric antigen; cd27 gene; fatty acid binding protein 4; fatty acid-binding proteins; fatty acid binding protein 5; transgelin 2; fabp5 protein, human; actb gene; ccl3 gene; ccl4 gene; ccr7 gene; cd28 gene; cst7 gene; cxcr5 gene; ern1 gene; gzmk gene; ifng gene; il7r gene; sell gene; tcf7 gene |
| Journal Title: | Nature |
| Volume: | 635 |
| Issue: | 8040 |
| ISSN: | 0028-0836 |
| Publisher: | Nature Publishing Group |
| Date Published: | 2024-11-28 |
| Start Page: | 1010 |
| End Page: | 1018 |
| Language: | English |
| DOI: | 10.1038/s41586-024-08071-y |
| PUBMED: | 39443795 |
| PROVIDER: | scopus |
| PMCID: | PMC11949091 |
| DOI/URL: | |
| Notes: | Source: Scopus |
