Linoleic acid potentiates CD8 T cell metabolic fitness and antitumor immunity.

Timo Peters, Simona Rodighiero, Ignazio Caruana, Simone Cardaci, Johannes B Huppa, Philip D Greenberg, Andrea Raimondi, Liam A McDonnell, Paola Vacca, Nicola Tumino, Giovanni Signore, Andreas Beilhack, Angela M Rizzo, Francesco Greco, Ayush T Raman, Zeinab Mokhtari, Dalia Sheta, Lukas Scheller, Alessia Loffreda, Stefan Ebert, Markus Machwirth, Punit Tyagi, Federica Conte, Paola A Corsetto, Silvia Tiberti, Carina B Nava Lauson, Teresa Manzo, Luigi Nezi

Journal: Cell metabolism 2023;35(4):633-650.e9

PMID: 36898381

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Abstract

The metabolic state represents a major hurdle for an effective adoptive T cell therapy (ACT). Indeed, specific lipids can harm CD8 T cell (CTL) mitochondrial integrity, leading to defective antitumor responses. However, the extent to which lipids can affect the CTL functions and fate remains unexplored. Here, we show that linoleic acid (LA) is a major positive regulator of CTL activity by improving metabolic fitness, preventing exhaustion, and stimulating a memory-like phenotype with superior effector functions. We report that LA treatment enhances the formation of ER-mitochondria contacts (MERC), which in turn promotes calcium (Ca) signaling, mitochondrial energetics, and CTL effector functions. As a direct consequence, the antitumor potency of LA-instructed CD8 T cells is superior in vitro and in vivo. We thus propose LA treatment as an ACT potentiator in tumor therapy.

Address: Department of Experimental Oncology, Istituto Europeo di Oncologia IRCCS, Milano, Italy.; Department of Pharmacological and Biomolecular Sciences, University of Milan, Milan, Italy.; Institute for Systems Analysis and Computer Science "Antonio Ruberti," National Research Council, Rome, Italy.; Department of Paediatric Haematology, Oncology and Stem Cell Transplantation, University Hospital of Würzburg, Würzburg, Germany.; Experimental Imaging Center, IRCCS San Raffaele Scientific Institute, San Raffaele Vita-Salute University, Milano, Italy.; Interdisciplinary Center for Clinical Research (IZKF), Experimental Stem Cell Transplantation Laboratory, Würzburg University Hospital, Würzburg, Germany.; Medical University of Vienna, Center for Pathophysiology, Infectiology and Immunology, Institute for Hygiene and Applied Immunology, Vienna, Austria.; Broad Institute of MIT and Harvard, Cambridge, MA, USA.; Fondazione Pisana per la Scienza, ONLUS, San Giuliano Terme, Italy; Institute of Life Sciences, Sant' Anna School of Advanced Studies, Pisa, Italy.; Fondazione Pisana per la Scienza, ONLUS, San Giuliano Terme, Italy.; Immunology Research Area, Innate Lymphoid Cells Unit, Bambino Gesù Children's Hospital IRCCS, Rome, Italy.; Clinical Research Division and Program in Immunology, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.; Division of Genetics and Cell Biology, IRCCS San Raffaele Scientific Institute, Milan, Italy.; Department of Experimental Oncology, Istituto Europeo di Oncologia IRCCS, Milano, Italy. Electronic address: [email protected].

DOI: 10.1016/j.cmet.2023.02.013

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https://assays.cancer.gov/CPTAC-177

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https://antibodies.cancer.gov/detail/CPTC-CD8A-1

MeSH Terms: Linoleic Acid, CD8-Positive T-Lymphocytes, Signal Transduction