ATM regulates differentiation of myofibroblastic cancer-associated fibroblasts and can be targeted to overcome immunotherapy resistance

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 SayanJason L Parsons, Stephen Durant, Gareth J Thomas*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

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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.

SIGNIFICANCE: 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.

Original languageEnglish
Pages (from-to)4571-4585
Number of pages15
JournalCancer Research
Volume82
Issue number24
DOIs
Publication statusPublished - 16 Dec 2022

Bibliographical note

©2022 The Authors; Published by the American Association for Cancer Research.

Keywords

  • Humans
  • Ataxia Telangiectasia Mutated Proteins/metabolism
  • Cancer-Associated Fibroblasts/metabolism
  • Cell Differentiation
  • Immunotherapy
  • Myofibroblasts/metabolism
  • Neoplasms
  • Drug Resistance, Neoplasm

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