GSE161922
ATM inhibition enhances cancer immunotherapy by promoting mtDNA leakage/cGAS-STING activation [B16 vivo]
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. Overall design: mRNA profiles of vector control and ATM KO B16 murine in vivo melanomas