황성민 (Weill Cornell Medicine, Cornell University) | 상위피인용논문 > 한빛사

한빛사논문, 상위피인용논문

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Weill Cornell Medicine, Cornell University

Nature, 23 October 2024 | https://doi.org/10.1038/s41586-024-08071-y Transgelin 2 guards T cell lipid metabolism and antitumour function

Sung-Min Hwang ^1,2, Deepika Awasthi ^1,2, Jieun Jeong ³, Tito A. Sandoval ^1,2, Chang-Suk Chae ^1,2,15, Yusibeska Ramos ¹, Chen Tan ^1,2, Matías Marin Falco ⁴, Camilla Salvagno ^1,2, Alexander Emmanuelli ^1,2,5, Ian T. McBain ⁵, Bikash Mishra^5,6, Lionel B. Ivashkiv ^5,6, Dmitriy Zamarin ⁷, Evelyn Cantillo^1,2, Eloise Chapman-Davis ^1,2, Kevin Holcomb ^1,2, Diana K. Morales ¹, Xiaoqing Yu⁸, Paulo C. Rodriguez ⁸, Jose R. Conejo-Garcia ^9,10, Martin Kaczocha ^11,12,13, Anna Vähärautio ^4,14, Minkyung Song ^1,2,16 & Juan R. Cubillos-Ruiz ^1,2,5 ,*

¹Department of Obstetrics and Gynecology, Weill Cornell Medicine, New York, NY, USA.
²Sandra and Edward Meyer Cancer Center, Weill Cornell Medicine, New York, NY, USA.
³Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
⁴Research Program in Systems Oncology, Research Programs Unit, Faculty of Medicine, University of Helsinki, Helsinki, Finland.
⁵Weill Cornell Graduate School of Medical Sciences, New York, NY, USA.
⁶HSS Research Institute and David Z. Rosensweig Genomics Research Center, Hospital for Special Surgery, New York, NY, USA.
⁷Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
⁸Department of Immunology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA.
⁹Department of Integrated Immunobiology, Duke School of Medicine, Durham, NC, USA.
¹⁰Duke Cancer Institute, Duke School of Medicine, Durham, NC, USA.
¹¹Department of Anesthesiology, Renaissance School of Medicine, Stony Brook University, Stony Brook, NY, USA.
¹²Institute of Chemical Biology and Drug Discovery, Stony Brook University, Stony Brook, NY, USA.
¹³Stony Brook University Pain and Analgesia Research Center (SPARC), Renaissance School of Medicine, Stony Brook University, Stony Brook, NY, USA.
¹⁴Foundation for the Finnish Cancer Institute, Helsinki, Finland.
¹⁵Present address: Research Institute, National Cancer Center, Goyang, Republic of Korea.
¹⁶Present address: Departments of Integrative Biotechnology and of Biopharmaceutical Convergence, Sungkyunkwan University, Suwon, Republic of Korea.

^*Corresponding author: correspondence to Juan R. Cubillos-Ruiz

Abstract

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.

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