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

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<sub>L</sub>-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.

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Publication Details

Journal
Cell Death Discovery
Published
2024-09-30
DOI
https://doi.org/10.1038/s41420-024-02184-z
Citations
22
Primary Topic
Cancer, Lipids, and Metabolism
Type
article
Field-Weighted Citation Impact
6.27

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

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article

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

Ruth Lupu, Miguel Ángel Pujana, Josep Sardanyés, Joaquim Bosch‐Barrera, Miguel Ángel Pardo-Cea, Begoña Martı́n-Castillo, Eila Serrano‐Hervás, Elisabet Cuyàs, Àngela Llop‐Hernández, Roderic Espín, Sara Verdura, Javier A. Menéndez, Tomás Alarcón, Eduard Teixidor, Eugeni López‐Bonet, Stefano Pedarra
article en
22 citations

Abstract

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<sub>L</sub>-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.

Cell Death DiscoveryVol. 10(1)
Institució Catalana de Recerca i Estudis Avançats (ES), Universitat Autònoma de Barcelona (ES), Mayo Clinic (US), Universitat de Girona (ES), Catalan Institute for Water Research (ES), Institut d'Investigació Biomédica de Bellvitge (ES), Institut Català d'Oncologia (ES), Institut d'Investigació Biomèdica de Girona (ES), Centre de Recerca Matemàtica (ES), Hospital Universitari de Girona Doctor Josep Trueta (ES)
U.S. Department of Defense, Centres de Recerca de Catalunya, Generalitat de Catalunya, Ministerio de Ciencia e Innovación, National Institutes of Health, Engineering and Physical Sciences Research Council, Agència de Gestió d'Ajuts Universitaris i de Recerca, Instituto de Salud Carlos III, European Regional Development Fund, Agencia Estatal de Investigación, National Cancer Institute, Division of Mathematical Sciences
Good health and well-being
Openalex Percentile: Top 3%
Cancer, Lipids, and Metabolism
6.27
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