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ATM inhibition enhances cancer immunotherapy by promoting mtDNA leakage/cGAS-STING activation [4T1 in vitro]

ABSTRACT: Novel approaches are needed to boost the efficacy of immune checkpoint blockade (ICB) therapy. Ataxia Telangiectasia Mutated (ATM) protein plays a central role in sensing DNA double strand breaks and coordinating their repair. Recent data indicated that ATM might be a promising target to enhance immune checkpoint blockade (ICB) therapy. However, the molecular mechanism involved is not clearly elucidated. Here we show that ATM inhibition could potentiate ICB therapy by promoting cytoplasmic leakage of mitochondrial DNA and activation of the cGAS/STING pathway. Genetic depletion of ATM in murine cancer cells significantly delayed tumor growth in syngeneic mouse hosts in a T-cell dependent manner. Furthermore, chemical inhibition of ATM significantly potentiated anti-PD1 therapy of mouse tumors. ATM inhibition potently activated the cGAS/STING pathway and enhanced lymphocyte infiltration into the tumor microenvironment by downregulating TFAM, which led to mitochondrial DNA leakage into the cytoplasm. Moreover, our analysis of data from a large patient cohort indicated that ATM mutations, especially nonsense mutations, predicted for clinical benefits for ICB therapy. Our study therefore provides strong evidence that ATM may serve both as a therapeutic target and a biomarker to enable ICB therapy.

ORGANISM(S): Mus musculus

PROVIDER: GSE161912 | GEO | 2023/11/18

REPOSITORIES: GEO

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ATM inhibition enhances cancer immunotherapy by promoting mtDNA leakage/cGAS-STING activation [B16 vivo]

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