ATM inhibition enhances cancer immunotherapy by promoting mtDNA leakage and cGAS/STING activation
Mengjie Hu, Min Zhou, Xuhui Bao, Dong Pan, Meng Jiao, Xinjian Liu, Fang Li, Chuan-Yuan Li
Mengjie Hu, Min Zhou, Xuhui Bao, Dong Pan, Meng Jiao, Xinjian Liu, Fang Li, Chuan-Yuan Li
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Research Article Oncology

ATM inhibition enhances cancer immunotherapy by promoting mtDNA leakage and cGAS/STING activation

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-stranded breaks (DSBs) and coordinating their repair. Recent data indicated that ATM might be a promising target to enhance ICB therapy. However, the molecular mechanism involved has not been clearly elucidated. Here, we show that ATM inhibition could potentiate ICB therapy by promoting cytoplasmic leakage of mitochondrial DNA (mtDNA) and activation of the cGAS/STING pathway. We show that genetic depletion of ATM in murine cancer cells delayed tumor growth in syngeneic mouse hosts in a T cell–dependent manner. Furthermore, chemical inhibition of ATM potentiated anti–PD-1 therapy of mouse tumors. ATM inhibition potently activated the cGAS/STING pathway and enhanced lymphocyte infiltration into the tumor microenvironment by downregulating mitochondrial transcription factor A (TFAM), which led to mtDNA 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 of ICB therapy. Our study therefore provides strong evidence that ATM may serve as both a therapeutic target and a biomarker to enable ICB therapy.

Authors

Mengjie Hu, Min Zhou, Xuhui Bao, Dong Pan, Meng Jiao, Xinjian Liu, Fang Li, Chuan-Yuan Li

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Figure 1

ATM inhibition induces a significant tumor growth delay and overcomes tumor resistance to anti–PD-1 therapy.

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ATM inhibition induces a significant tumor growth delay and overcomes tu...
(A and B) Tumor volume and Kaplan-Meier survival curves for BALB/c mice inoculated with approximately 2 × 105 vector control (VC) or Atm-KO 4T1 cells. (C and D) Tumor volume and Kaplan-Meier survival curves for naive and previously challenged but tumor-free BALB/C mice after rechallenge with 1 × 105 WT 4T1 tumor cells. Tumor-free BALB/C mice were rechallenged after remaining tumor free 40 days following the initial inoculation with Atm-KO 4T1 cells. (E and F)Tumor volume and Kaplan-Meier survival curves for C57BL/6 mice inoculated with approximately 1 × 105 vector control or Atm-KO B16F10 (B16) cells and treated with 100 μg/mouse anti–PD-1 or isotype control antibodies on days 6, 9, and 12 after inoculation. (G and H) Tumor volume and Kaplan-Meier survival curves for C57BL/6 mice inoculated with approximately 1 × 105 B16F10 cells and treated with 100 μg/mouse anti–PD-1 or isotype control antibodies on days 6, 9, and 12 and with AZD1390 (AZD) (10 mg/kg) or vehicle (Veh) daily on days 4–14. Data are from 2 independent experiments. (I and J) Tumor volume and Kaplan-Meier survival curves for BALB/c mice inoculated with approximately 1 × 105 4T1 cells and treated with 100 μg/mouse anti–PD-1 antibodies or isotype control on days 6, 9, and 12 and with AZD1390 (10 mg/kg) or vehicle daily on days 4–14. Data represent the mean ± SEM. *P < 0.05, **P < 0.01, and ****P < 0.0001, by unpaired t test (A, C, E, G, and I) or log-rank test (B, D, F, H, and J).