Transgelin 2 guards T cell lipid metabolism and antitumour function.

Autor: Hwang SM; Department of Obstetrics and Gynecology, Weill Cornell Medicine, New York, NY, USA.; Sandra and Edward Meyer Cancer Center, Weill Cornell Medicine, New York, NY, USA., Awasthi D; Department of Obstetrics and Gynecology, Weill Cornell Medicine, New York, NY, USA.; Sandra and Edward Meyer Cancer Center, Weill Cornell Medicine, New York, NY, USA., Jeong J; Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA., Sandoval TA; Department of Obstetrics and Gynecology, Weill Cornell Medicine, New York, NY, USA.; Sandra and Edward Meyer Cancer Center, Weill Cornell Medicine, New York, NY, USA., Chae CS; Department of Obstetrics and Gynecology, Weill Cornell Medicine, New York, NY, USA.; Sandra and Edward Meyer Cancer Center, Weill Cornell Medicine, New York, NY, USA.; Research Institute, National Cancer Center, Goyang, Republic of Korea., Ramos Y; Department of Obstetrics and Gynecology, Weill Cornell Medicine, New York, NY, USA., Tan C; Department of Obstetrics and Gynecology, Weill Cornell Medicine, New York, NY, USA.; Sandra and Edward Meyer Cancer Center, Weill Cornell Medicine, New York, NY, USA., Marin Falco M; Research Program in Systems Oncology, Research Programs Unit, Faculty of Medicine, University of Helsinki, Helsinki, Finland., Salvagno C; Department of Obstetrics and Gynecology, Weill Cornell Medicine, New York, NY, USA.; Sandra and Edward Meyer Cancer Center, Weill Cornell Medicine, New York, NY, USA., Emmanuelli A; Department of Obstetrics and Gynecology, Weill Cornell Medicine, New York, NY, USA.; Sandra and Edward Meyer Cancer Center, Weill Cornell Medicine, New York, NY, USA.; Weill Cornell Graduate School of Medical Sciences, New York, NY, USA., McBain IT; Weill Cornell Graduate School of Medical Sciences, New York, NY, USA., Mishra B; Weill Cornell Graduate School of Medical Sciences, New York, NY, USA.; HSS Research Institute and David Z. Rosensweig Genomics Research Center, Hospital for Special Surgery, New York, NY, USA., Ivashkiv LB; Weill Cornell Graduate School of Medical Sciences, New York, NY, USA.; HSS Research Institute and David Z. Rosensweig Genomics Research Center, Hospital for Special Surgery, New York, NY, USA., Zamarin D; Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA., Cantillo E; Department of Obstetrics and Gynecology, Weill Cornell Medicine, New York, NY, USA.; Sandra and Edward Meyer Cancer Center, Weill Cornell Medicine, New York, NY, USA., Chapman-Davis E; Department of Obstetrics and Gynecology, Weill Cornell Medicine, New York, NY, USA.; Sandra and Edward Meyer Cancer Center, Weill Cornell Medicine, New York, NY, USA., Holcomb K; Department of Obstetrics and Gynecology, Weill Cornell Medicine, New York, NY, USA.; Sandra and Edward Meyer Cancer Center, Weill Cornell Medicine, New York, NY, USA., Morales DK; Department of Obstetrics and Gynecology, Weill Cornell Medicine, New York, NY, USA., Yu X; Department of Immunology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA., Rodriguez PC; Department of Immunology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA., Conejo-Garcia JR; Department of Integrated Immunobiology, Duke School of Medicine, Durham, NC, USA.; Duke Cancer Institute, Duke School of Medicine, Durham, NC, USA., Kaczocha M; Department of Anesthesiology, Renaissance School of Medicine, Stony Brook University, Stony Brook, NY, USA.; Institute of Chemical Biology and Drug Discovery, Stony Brook University, Stony Brook, NY, USA.; Stony Brook University Pain and Analgesia Research Center (SPARC), Renaissance School of Medicine, Stony Brook University, Stony Brook, NY, USA., Vähärautio A; Research Program in Systems Oncology, Research Programs Unit, Faculty of Medicine, University of Helsinki, Helsinki, Finland.; Foundation for the Finnish Cancer Institute, Helsinki, Finland., Song M; Department of Obstetrics and Gynecology, Weill Cornell Medicine, New York, NY, USA.; Sandra and Edward Meyer Cancer Center, Weill Cornell Medicine, New York, NY, USA.; Departments of Integrative Biotechnology and of Biopharmaceutical Convergence, Sungkyunkwan University, Suwon, Republic of Korea., Cubillos-Ruiz JR; Department of Obstetrics and Gynecology, Weill Cornell Medicine, New York, NY, USA. jur2016@med.cornell.edu.; Sandra and Edward Meyer Cancer Center, Weill Cornell Medicine, New York, NY, USA. jur2016@med.cornell.edu.; Weill Cornell Graduate School of Medical Sciences, New York, NY, USA. jur2016@med.cornell.edu.
Jazyk: angličtina
Zdroj: Nature [Nature] 2024 Nov; Vol. 635 (8040), pp. 1010-1018. Date of Electronic Publication: 2024 Oct 23.
DOI: 10.1038/s41586-024-08071-y
Abstrakt: 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.
Competing Interests: Competing interests: J.R.C.-R. holds patents on the targeting of ER stress responses for the treatment of disease, as well as on the use of immune modulators for OC therapy. J.R.C.-R. is a scientific consultant for Moderna, Immagene, Autoimmunity Biologic Solutions, and Emerald Bioventures, and holds stock options in Vescor Therapeutics. D.Z. reports institutional grants from Merck, Genentech, AstraZeneca, Plexxikon, and Synthekine, and personal fees from AstraZeneca, Xencor, Memgen, Takeda, Synthekine, Immunos, Tessa Therapeutics, Miltenyi, and Calidi Biotherapeutics. D.Z. owns a patent on use of oncolytic Newcastle Disease Virus for cancer therapy. J.R.C.-G. has stock options in Compass Therapeutics, Anixa Biosciences, and Alloy Therapeutics; receives licensing fees from Anixa Biosciences for the patent of FSHCER T cells; receives honorarium from Alloy Therapeutics; has intellectual property with Compass Therapeutics and Anixa Biosciences; and is co-founder of Cellepus Therapeutics, a company that develops allogeneic γδ CAR T cells. All other authors declare no potential conflicts of interest.
(© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)
Databáze: MEDLINE
Externí odkaz: