Transgelin 2 guards T cell lipid metabolism and antitumour function

Sung-Min Hwang, Deepika Awasthi, Jieun Jeong, Tito A. Sandoval, Chang-Suk Chae, Yusibeska Ramos, Chen Tan, Matías Marin Falco, Camilla Salvagno, Alexander Emmanuelli, Ian T. McBain, Bikash Mishra, Lionel B. Ivashkiv, Dmitriy Zamarin, Evelyn Cantillo, Eloise Chapman-Davis, Kevin Holcomb, Diana K. Morales, Xiaoqing Yu, Paulo C. Rodriguez, Jose R. Conejo-Garcia, Martin Kaczocha, Anna Vähärautio, Minkyung Song and Juan R. Cubillos-Ruiz ()
Additional contact information
Sung-Min Hwang: Weill Cornell Medicine
Deepika Awasthi: Weill Cornell Medicine
Jieun Jeong: Memorial Sloan Kettering Cancer Center
Tito A. Sandoval: Weill Cornell Medicine
Chang-Suk Chae: Weill Cornell Medicine
Yusibeska Ramos: Weill Cornell Medicine
Chen Tan: Weill Cornell Medicine
Matías Marin Falco: University of Helsinki
Camilla Salvagno: Weill Cornell Medicine
Alexander Emmanuelli: Weill Cornell Medicine
Ian T. McBain: Weill Cornell Graduate School of Medical Sciences
Bikash Mishra: Weill Cornell Graduate School of Medical Sciences
Lionel B. Ivashkiv: Weill Cornell Graduate School of Medical Sciences
Dmitriy Zamarin: Icahn School of Medicine at Mount Sinai
Evelyn Cantillo: Weill Cornell Medicine
Eloise Chapman-Davis: Weill Cornell Medicine
Kevin Holcomb: Weill Cornell Medicine
Diana K. Morales: Weill Cornell Medicine
Xiaoqing Yu: H. Lee Moffitt Cancer Center and Research Institute
Paulo C. Rodriguez: H. Lee Moffitt Cancer Center and Research Institute
Jose R. Conejo-Garcia: Duke School of Medicine
Martin Kaczocha: Stony Brook University
Anna Vähärautio: University of Helsinki
Minkyung Song: Weill Cornell Medicine
Juan R. Cubillos-Ruiz: Weill Cornell Medicine

Nature, 2024, vol. 635, issue 8040, 1010-1018

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41586-024-08071-y

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