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Supplementary Data 5 from ATM Regulates Differentiation of Myofibroblastic Cancer-Associated Fibroblasts and Can Be Targeted to Overcome Immunotherapy Resistance

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posted on 2023-03-31, 05:40 authored by Massimiliano Mellone, Klaudia Piotrowska, Giulia Venturi, Lija James, Aleksandra Bzura, Maria A. Lopez, Sonya James, Chuan Wang, Matthew J. Ellis, Christopher J. Hanley, Josephine F. Buckingham, Kerry L. Cox, Gareth Hughes, Viia Valge-Archer, Emma V. King, Stephen A. Beers, Vincent Jaquet, George D.D. Jones, Natalia Savelyeva, Emre Sayan, Jason L. Parsons, Stephen Durant, Gareth J. Thomas

Non-redundant list of the leading-edge genes and ToppFun pathway analysis from the genesets in Suppl. File 4 used to make the DDR-TGFB_signature geneset

Funding

Cancer Research UK (CRUK)

Rosetrees Trust (Rosetrees)

Wessex Medical Research (WMR)

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ARTICLE ABSTRACT

Myofibroblastic cancer-associated fibroblast (myoCAF)–rich tumors generally contain few T cells and respond poorly to immune-checkpoint blockade. Although myoCAFs are associated with poor outcome in most solid tumors, the molecular mechanisms regulating myoCAF accumulation remain unclear, limiting the potential for therapeutic intervention. Here, we identify ataxia-telangiectasia mutated (ATM) as a central regulator of the myoCAF phenotype. Differentiating myofibroblasts in vitro and myoCAFs cultured ex vivo display activated ATM signaling, and targeting ATM genetically or pharmacologically could suppress and reverse differentiation. ATM activation was regulated by the reactive oxygen species–producing enzyme NOX4, both through DNA damage and increased oxidative stress. Targeting fibroblast ATM in vivo suppressed myoCAF-rich tumor growth, promoted intratumoral CD8 T-cell infiltration, and potentiated the response to anti–PD-1 blockade and antitumor vaccination. This work identifies a novel pathway regulating myoCAF differentiation and provides a rationale for using ATM inhibitors to overcome CAF-mediated immunotherapy resistance. ATM signaling supports the differentiation of myoCAFs to suppress T-cell infiltration and antitumor immunity, supporting the potential clinical use of ATM inhibitors in combination with checkpoint inhibition in myoCAF-rich, immune-cold tumors.

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    Cancer Research

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    cancer

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