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; Juan R Cubillos-Ruiz

doi:10.1038/s41586-024-08071-y

Transgelin 2 guards T cell lipid metabolism and antitumour function

Nature. 2024 Oct 23. doi: 10.1038/s41586-024-08071-y. Online ahead of print.

Authors

Sung-Min Hwang^{1

2}, Deepika Awasthi^{1

2}, Jieun Jeong³, Tito A Sandoval^{1

2}, Chang-Suk Chae^{1

2

4}, Yusibeska Ramos¹, Chen Tan^{1

2}, Matías Marin Falco⁵, Camilla Salvagno^{1

2}, Alexander Emmanuelli^{1

2

6}, Ian T McBain⁶, Bikash Mishra^{6

7}, Lionel B Ivashkiv^{6

7}, Dmitriy Zamarin⁸, Evelyn Cantillo^{1

2}, Eloise Chapman-Davis^{1

2}, Kevin Holcomb^{1

2}, Diana K Morales¹, Xiaoqing Yu⁹, Paulo C Rodriguez⁹, Jose R Conejo-Garcia^{10

11}, Martin Kaczocha^{12

13

14}, Anna Vähärautio^{5

15}, Minkyung Song^{1

2

16}, Juan R Cubillos-Ruiz^{17

18

19}

Affiliations

¹ Department of Obstetrics and Gynecology, Weill Cornell Medicine, New York, NY, USA.
² Sandra and Edward Meyer Cancer Center, Weill Cornell Medicine, New York, NY, USA.
³ Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
⁴ Research Institute, National Cancer Center, Goyang, Republic of Korea.
⁵ Research Program in Systems Oncology, Research Programs Unit, Faculty of Medicine, University of Helsinki, Helsinki, Finland.
⁶ Weill Cornell Graduate School of Medical Sciences, New York, NY, USA.
⁷ HSS Research Institute and David Z. Rosensweig Genomics Research Center, Hospital for Special Surgery, New York, NY, USA.
⁸ Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
⁹ Department of Immunology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA.
¹⁰ Department of Integrated Immunobiology, Duke School of Medicine, Durham, NC, USA.
¹¹ Duke Cancer Institute, Duke School of Medicine, Durham, NC, USA.
¹² Department of Anesthesiology, Renaissance School of Medicine, Stony Brook University, Stony Brook, NY, USA.
¹³ Institute of Chemical Biology and Drug Discovery, Stony Brook University, Stony Brook, NY, USA.
¹⁴ Stony Brook University Pain and Analgesia Research Center (SPARC), Renaissance School of Medicine, Stony Brook University, Stony Brook, NY, USA.
¹⁵ Foundation for the Finnish Cancer Institute, Helsinki, Finland.
¹⁶ Departments of Integrative Biotechnology and of Biopharmaceutical Convergence, Sungkyunkwan University, Suwon, Republic of Korea.
¹⁷ Department of Obstetrics and Gynecology, Weill Cornell Medicine, New York, NY, USA. [email protected].
¹⁸ Sandra and Edward Meyer Cancer Center, Weill Cornell Medicine, New York, NY, USA. [email protected].
¹⁹ Weill Cornell Graduate School of Medical Sciences, New York, NY, USA. [email protected].

PMID: 39443795
DOI: 10.1038/s41586-024-08071-y

Abstract

Mounting effective immunity against pathogens and tumours relies on the successful metabolic programming of T cells by extracellular fatty acids^1-3. 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 cells^4,5. 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.