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

Publication ,  Journal Article
Hwang, S-M; Awasthi, D; Jeong, J; Sandoval, TA; Chae, C-S; Ramos, Y; Tan, C; Falco, MM; McBain, IT; Mishra, B; Ivashkiv, LB; Zamarin, D ...
Published in: Res Sq
December 14, 2023

Mounting effective immunity against pathogens and tumors relies on the successful metabolic programming of T cells by extracellular fatty acids1-3. During this process, fatty-acid-binding protein 5 (FABP5) imports lipids that fuel mitochondrial respiration and sustain the bioenergetic requirements of protective CD8+ T cells4,5. 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.

Duke Scholars

Published In

Res Sq

DOI

EISSN

2693-5015

Publication Date

December 14, 2023

Location

United States
 

Citation

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Hwang, S.-M., Awasthi, D., Jeong, J., Sandoval, T. A., Chae, C.-S., Ramos, Y., … Cubillos-Ruiz, J. R. (2023). Transgelin 2 guards T cell lipid metabolic programming and anti-tumor function. Res Sq. https://doi.org/10.21203/rs.3.rs-3683989/v1
Hwang, Sung-Min, Deepika Awasthi, Jieun Jeong, Tito A. Sandoval, Chang-Suk Chae, Yusibeska Ramos, Chen Tan, et al. “Transgelin 2 guards T cell lipid metabolic programming and anti-tumor function.Res Sq, December 14, 2023. https://doi.org/10.21203/rs.3.rs-3683989/v1.
Hwang S-M, Awasthi D, Jeong J, Sandoval TA, Chae C-S, Ramos Y, et al. Transgelin 2 guards T cell lipid metabolic programming and anti-tumor function. Res Sq. 2023 Dec 14;
Hwang, Sung-Min, et al. “Transgelin 2 guards T cell lipid metabolic programming and anti-tumor function.Res Sq, Dec. 2023. Pubmed, doi:10.21203/rs.3.rs-3683989/v1.
Hwang S-M, Awasthi D, Jeong J, Sandoval TA, Chae C-S, Ramos Y, Tan C, Falco MM, McBain IT, Mishra B, Ivashkiv LB, Zamarin D, Cantillo E, Chapman-Davis E, Holcomb K, Morales DK, Rodriguez PC, Conejo-Garcia JR, Kaczocha M, Vähärautio A, Song M, Cubillos-Ruiz JR. Transgelin 2 guards T cell lipid metabolic programming and anti-tumor function. Res Sq. 2023 Dec 14;

Published In

Res Sq

DOI

EISSN

2693-5015

Publication Date

December 14, 2023

Location

United States