ATM inhibition enhances cancer immunotherapy by promoting mtDNA leakage/cGAS-STING activation
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ABSTRACT:
PROVIDER: PRJNA679827 | ENA |
REPOSITORIES: ENA
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Project description: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.
2023-11-18 | GSE161922 | GEO
Project description: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.
2023-11-18 | GSE161912 | GEO
Project description:ATM inhibition enhances cancer immunotherapy by promoting mtDNA leakage/cGAS-STING activation [B16 vivo]
| PRJNA679830 | ENA
Project description:ATM inhibition enhances cancer immunotherapy by promoting mtDNA leakage/cGAS-STING activation [4T1 in vitro]
| PRJNA679813 | ENA
Project description: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.
| S-EPMC7843232 | biostudies-literature
Project description:One of the most common metabolic defects of cancer cells is the deficiency in arginine synthesis due to suppressed expression of argininosuccinate synthetase 1 (ASS1) which renders cancer cells auxotrophic to external arginine supply. Arginine deprivation has been effectively used as a treatment for leukemias, with several clinical trials on solid tumors underway. We previously showed that in prostate cancer arginine depletion induced mitochondrial dysfunction and excessive ROS production resulting in chromatin autophagy, nuclear DNA leakage, and cellular death, but the detailed mechanism of arginine starvation-induced cell death remains unclear. In this study, we demonstrated that arginine deprivation coordinately suppressed metabolic genes, including those responsible for mitochondrial oxidative phosphorylation (OXPHOS), nucleotide metabolism, and DNA repair. The consequent ROS production and impaired DNA damage response resulted in nuclear DNA leakage and cGAS-STING activation which is accompanied by upregulation of type I interferon response. We also showed that coordinated silencing of OXPHOS and DNA repair genes is caused in part by the depletion of α-ketoglutarate (αKG) and inactivation of histone demethylases. Supplementing cell-permeable dimethyl α-ketoglutarate (DMKG) both reduced repressive histone methylations and partially restored OXPHOS gene expressions, mitochondrial functions, and mitigated nuclear DNA leakage. Using our dietary arginine-restriction model, we demonstrate that arginine starvation slows prostate cancer growth with evidence of enhanced interferon responses and recruitment of immune cells. Our data suggests arginine starvation induces cell killing of ASS1-low cancer cells by metabolic depletion and epigenetic silencing of metabolic genes, leading to DNA damage and leakage. Resulting cGAS-STING activation may further enhance these killing effects.
2021-06-28 | GSE151809 | GEO
Project description:One of the most common metabolic defects of cancer cells is the deficiency in arginine synthesis due to suppressed expression of argininosuccinate synthetase 1 (ASS1) which renders cancer cells auxotrophic to external arginine supply. Arginine deprivation has been effectively used as a treatment for leukemias, with several clinical trials on solid tumors underway. We previously showed that in prostate cancer arginine depletion induced mitochondrial dysfunction and excessive ROS production resulting in chromatin autophagy, nuclear DNA leakage, and cellular death, but the detailed mechanism of arginine starvation-induced cell death remains unclear. In this study, we demonstrated that arginine deprivation coordinately suppressed metabolic genes, including those responsible for mitochondrial oxidative phosphorylation (OXPHOS), nucleotide metabolism, and DNA repair. The consequent ROS production and impaired DNA damage response resulted in nuclear DNA leakage and cGAS-STING activation which is accompanied by upregulation of type I interferon response. We also showed that coordinated silencing of OXPHOS and DNA repair genes is caused in part by the depletion of α-ketoglutarate (αKG) and inactivation of histone demethylases. Supplementing cell-permeable dimethyl α-ketoglutarate (DMKG) both reduced repressive histone methylations and partially restored OXPHOS gene expressions, mitochondrial functions, and mitigated nuclear DNA leakage. Using our dietary arginine-restriction model, we demonstrate that arginine starvation slows prostate cancer growth with evidence of enhanced interferon responses and recruitment of immune cells. Our data suggests arginine starvation induces cell killing of ASS1-low cancer cells by metabolic depletion and epigenetic silencing of metabolic genes, leading to DNA damage and leakage. Resulting cGAS-STING activation may further enhance these killing effects. We used microarray to analyze the expression difference between control and arginine-depleted cells to find out what genes involved in the regulation of mitochondrial function and arginine deprivation-induced cell death.
2021-06-28 | GSE151719 | GEO
Project description:This SuperSeries is composed of the SubSeries listed below.
2023-11-18 | GSE161924 | GEO
Project description:Colorectal cancer is the second leading cause of cancer mortality in the US. Although immune checkpoint blockade therapies such as anti-PD-1/PD-L1 have had successes in some patients, the response rate is still low. We have found that riluzole, a well-tolerated FDA-approved oral medicine for treating amyotrophic lateral sclerosis, increased intratumoral CD8+ T cells and suppressed tumor growth of colon cancer cells in syngeneic immune competent mice. Riluzole-mediated tumor suppression was dependent on the presence of CD8+ T cells. Riluzole activates the cytosolic DNA sensing cGAS/STING pathway and increases expression of interferon β (IFNβ) and IFNβ-regulated genes including CXCL10. Inhibition of ATM, but not ATR, results in a synergistic increase in IFNβ expression, suggesting that riluzole-dependent double strand breaks contribute to cGAS/STING activation. Knockout of cGAS or STING significantly attenuated expression of IFNβ and CXCL10 and nearly abolished suppression of tumor growth. Riluzole failed to increase intratumoral CD8+ T cells in STING knockout tumors. These results indicate that riluzole recruits CD8+ T cells into the tumor microenvironment through tumor cell intrinsic STING activation. When riluzole was combined with a PD-1 antibody, the treatment was more effective in suppressing tumor growth in vivo. Taken together, our studies indicate that riluzole inhibits tumor growth through the activation of cGAS/STING signaling and may increase the efficacy of anti-PD-1/PD-L1 therapies in colon cancer.
2024-09-27 | GSE251940 | GEO
Project description:Low-grade inflammation is a hallmark of old age and a central driver of ageing-associated impairment and disease. Multiple factors can contribute to ageing-associated inflammation, however the molecular pathways transducing aberrant inflammatory signalling and their impact in natural ageing remain poorly understood. Here we show that the cGAS-STING signalling pathway, mediating immune sensing of DNA, is a critical driver of chronic inflammation and functional decline during ageing. Blockade of STING suppresses the inflammatory phenotypes of senescent human cells and tissues, attenuates ageing-related inflammation in multiple peripheral organs and the brain in mice, and leads to an improvement in tissue function. Focusing on the ageing brain, we reveal that activation of STING triggers reactive microglia transcriptional states, neurodegeneration and cognitive decline. Cytosolic DNA released from perturbed mitochondria elicits cGAS activity in old microglia defining a mechanism by which cGAS-STING signalling is engaged in the ageing brain. Single-nuclei RNA-sequencing (snRNA-seq) of microglia and hippocampi of a newly developed cGAS gain-of-function mouse model demonstrates that engagement of cGAS in microglia is sufficient to direct ageing-associated transcriptional microglia states leading to bystander cell inflammation, neurotoxicity and impaired memory capacity. Our findings establish the cGAS-STING pathway as a critical driver of ageing-related inflammation in peripheral organs and the brain, and reveal blockade of cGAS-STING signalling as a potential strategy to halt (neuro)degenerative processes during old age.
2023-08-20 | GSE234420 | GEO