Fatty acid synthase (FASN) is a tumor-cell-intrinsic metabolic checkpoint restricting T-cell immunity.

Autor: Cuyàs E; Program Against Cancer Therapeutic Resistance (ProCURE), Catalan Institute of Oncology, 17007, Girona, Spain.; Metabolism and Cancer Group, Girona Biomedical Research Institute (IDIBGI), 17190, Girona, Spain., Pedarra S; Centre de Recerca Matemàtica (CRM), 08193, Bellaterra, Barcelona, Spain., Verdura S; Program Against Cancer Therapeutic Resistance (ProCURE), Catalan Institute of Oncology, 17007, Girona, Spain.; Metabolism and Cancer Group, Girona Biomedical Research Institute (IDIBGI), 17190, Girona, Spain., Pardo MA; ProCURE, Catalan Institute of Oncology, Oncobell, Bellvitge Institute for Biomedical Research (IDIBELL), 08908 L'Hospitalet de Llobregat, Barcelona, Spain., Espin Garcia R; ProCURE, Catalan Institute of Oncology, Oncobell, Bellvitge Institute for Biomedical Research (IDIBELL), 08908 L'Hospitalet de Llobregat, Barcelona, Spain., Serrano-Hervás E; Program Against Cancer Therapeutic Resistance (ProCURE), Catalan Institute of Oncology, 17007, Girona, Spain.; Metabolism and Cancer Group, Girona Biomedical Research Institute (IDIBGI), 17190, Girona, Spain., Llop-Hernández À; Program Against Cancer Therapeutic Resistance (ProCURE), Catalan Institute of Oncology, 17007, Girona, Spain.; Metabolism and Cancer Group, Girona Biomedical Research Institute (IDIBGI), 17190, Girona, Spain., Teixidor E; Medical Oncology, Catalan Institute of Oncology, 17007, Girona, Spain.; Precision Oncology Group (OncoGir-Pro), Girona Biomedical Research Institute (IDIBGI), 17190, Girona, Spain., Bosch-Barrera J; Medical Oncology, Catalan Institute of Oncology, 17007, Girona, Spain.; Precision Oncology Group (OncoGir-Pro), Girona Biomedical Research Institute (IDIBGI), 17190, Girona, Spain.; Department of Medical Sciences, Medical School, University of Girona, 17071, Girona, Spain., López-Bonet E; Metabolism and Cancer Group, Girona Biomedical Research Institute (IDIBGI), 17190, Girona, Spain.; Department of Anatomical Pathology, Dr. Josep Trueta Hospital of Girona, 17007, Girona, Spain., Martin-Castillo B; Metabolism and Cancer Group, Girona Biomedical Research Institute (IDIBGI), 17190, Girona, Spain.; Unit of Clinical Research, Catalan Institute of Oncology, 17007, Girona, Spain., Lupu R; Division of Experimental Pathology, Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, 55905, USA.; Mayo Clinic Cancer Center, Rochester, MN, 55905, USA.; Department of Biochemistry and Molecular Biology Laboratory, Mayo Clinic Laboratory, Rochester, MN, 55905, USA., Pujana MA; Program Against Cancer Therapeutic Resistance (ProCURE), Catalan Institute of Oncology, 17007, Girona, Spain.; ProCURE, Catalan Institute of Oncology, Oncobell, Bellvitge Institute for Biomedical Research (IDIBELL), 08908 L'Hospitalet de Llobregat, Barcelona, Spain., Sardanyès J; Centre de Recerca Matemàtica (CRM), 08193, Bellaterra, Barcelona, Spain., Alarcón T; Centre de Recerca Matemàtica (CRM), 08193, Bellaterra, Barcelona, Spain.; ICREA, 08010, Barcelona, Spain.; Departament de Matemàtiques, Universitat Autònoma de Barcelona, 08193, Bellaterra, Barcelona, Spain., Menendez JA; Program Against Cancer Therapeutic Resistance (ProCURE), Catalan Institute of Oncology, 17007, Girona, Spain. jmenendez@idibgi.org.; Metabolism and Cancer Group, Girona Biomedical Research Institute (IDIBGI), 17190, Girona, Spain. jmenendez@idibgi.org.
Jazyk: angličtina
Zdroj: Cell death discovery [Cell Death Discov] 2024 Sep 30; Vol. 10 (1), pp. 417. Date of Electronic Publication: 2024 Sep 30.
DOI: 10.1038/s41420-024-02184-z
Abstrakt: Fatty acid synthase (FASN)-catalyzed endogenous lipogenesis is a hallmark of cancer metabolism. However, whether FASN is an intrinsic mechanism of tumor cell defense against T cell immunity remains unexplored. To test this hypothesis, here we combined bioinformatic analysis of the FASN-related immune cell landscape, real-time assessment of cell-based immunotherapy efficacy in CRISPR/Cas9-based FASN gene knockout (FASN KO) cell models, and mathematical and mechanistic evaluation of FASN-driven immunoresistance. FASN expression negatively correlates with infiltrating immune cells associated with cancer suppression, cytolytic activity signatures, and HLA-I expression. Cancer cells engineered to carry a loss-of-function mutation in FASN exhibit an enhanced cytolytic response and an accelerated extinction kinetics upon interaction with cytokine-activated T cells. Depletion of FASN results in reduced carrying capacity, accompanied by the suppression of mitochondrial OXPHOS and strong downregulation of electron transport chain complexes. Targeted FASN depletion primes cancer cells for mitochondrial apoptosis as it synergizes with BCL-2/BCL-X L -targeting BH3 mimetics to render cancer cells more susceptible to T-cell-mediated killing. FASN depletion prevents adaptive induction of PD-L1 in response to interferon-gamma and reduces constitutive overexpression of PD-L1 by abolishing PD-L1 post-translational palmitoylation. FASN is a novel tumor cell-intrinsic metabolic checkpoint that restricts T cell immunity and may be exploited to improve the efficacy of T cell-based immunotherapy.
(© 2024. The Author(s).)
Databáze: MEDLINE
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