Similar Datasets
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: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
| PRJNA679827 | ENA
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:Macroautophagy decreases with age, and this change is considered a hallmark of the aging process. It remains unknown whether mitophagy, the essential selective autophagic degradation of mitochondria, also decreases with age. In our analysis of mitophagy in multiple organs in the mito-QC reporter mouse, mitophagy is either increased or unchanged in old versus young mice. Transcriptomic analysis shows marked upregulation of the type I interferon response in the retina of old mice, which correlates with increased levels of cytosolic mtDNA and activation of the cGAS/STING pathway. Crucially, these same alterations are replicated in primary human fibroblasts from elderly donors. In old mice, pharmacological induction of mitophagy with urolithin A attenuates cGAS/STING activation and ameliorates deterioration of neurological function. These findings point to mitophagy induction as a strategy to decrease age-associated inflammation and increase healthspan.
| S-EPMC10821893 | biostudies-literature
Project description:Immunotherapies that block PD-L1/PD-1 immune checkpoint proteins represent a landmark breakthrough in cancer treatment. Although the role of PD-L1 in suppressing T cell activity has been extensively studied, its cancer cell-intrinsic functions are not well understood. Herein, we demonstrated that PD-L1 is important for the repair of DNA damage in cancer cells. Mechanically, depletion of PD-L1 led to the downregulation of the critical molecules involved in the homologous recombination (HR) repair pathway, such as ATM and BRCA1, but did not obviously affect the non-homologous end joining (NHEJ) pathway. Notably, PD-L1 silence sensitized cancer cells to chemotherapy agents and the inhibitor of DNA-PK, which is an important kinase for NHEJ. Furthermore, PD-L1 depletion potentiated DNA damage-induced cGAS-STING pathway and induction of IFNβ. The regulation of DNA repair and cGAS-STING pathway by PD-L1 represents its connection with innate immunity that can be exploited to enhance the efficacy of existing immunotherapy. Our findings thus expand the focus of PD-L1 from tumor antigen-specific CD8+ T cells to innate immunity, and support targeting tumor-intrinsic PD-L1 combined with DNA-PK inhibition for tumor eradication, through promoting synthetic lethality and innate immune response.
| S-EPMC9185610 | biostudies-literature
Project description:ARID1A, a component of the chromatin-remodeling complex SWI/SNF, is one of the most frequently mutated genes in human cancer. We sought to develop rational combination therapy to potentiate the efficacy of immune checkpoint blockade in ARID1A-deficient tumors. In a proteomic analysis of a data set from The Cancer Genomic Atlas, we found enhanced expression of Chk2, a DNA damage checkpoint kinase, in ARID1A-mutated/deficient tumors. Surprisingly, we found that ARID1A targets the nonchromatin substrate Chk2 for ubiquitination. Loss of ARID1A increased the Chk2 level through modulating autoubiquitination of the E3-ligase RNF8 and thereby reducing RNF8-mediated Chk2 degradation. Inhibition of the ATM/Chk2 DNA damage checkpoint axis led to replication stress and accumulation of cytosolic DNA, which subsequently activated the DNA sensor STING-mediated innate immune response in ARID1A-deficient tumors. As expected, tumors with mutation or low expression of both ARID1A and ATM/Chk2 exhibited increased tumor-infiltrating lymphocytes and were associated with longer patient survival. Notably, an ATM inhibitor selectively potentiated the efficacy of immune checkpoint blockade in ARID1A-depleted tumors but not in WT tumors. Together, these results suggest that ARID1A's targeting of the nonchromatin substrate Chk2 for ubiquitination makes it possible to selectively modulate cancer cell-intrinsic innate immunity to enhance the antitumor activity of immune checkpoint blockade.
| S-EPMC7598069 | biostudies-literature
Project description:Background: Sterile inflammation contributes to the pathogenesis of cardiac dysfunction caused by various conditions including pressure overload in hypertension. Mitochondrial DNA (mtDNA) released from damaged mitochondria has been implicated in cardiac inflammation. However, the upstream mechanisms governing mtDNA release and how mtDNA activates sterile inflammation in pressure-overloaded hearts remain largely unknown. Here, we investigated the role of inducible NO synthase (iNOS) on pressure overload-induced cytosolic accumulation of mtDNA and whether mtDNA activated inflammation through the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway. Methods: To investigate whether the cGAS-STING cascade was involved in sterile inflammation and cardiac dysfunction upon pressure overload, cardiomyocyte-specific STING depletion mice and mice injected with adeno-associated virus-9 (AAV-9) to suppress the cGAS-STING cascade in the heart were subjected to transverse aortic constriction (TAC). iNOS null mice were used to determine the role of iNOS in cGAS-STING pathway activation in pressure-stressed hearts. Results: iNOS knockout abrogated mtDNA release and alleviated cardiac sterile inflammation resulting in improved cardiac function. Conversely, activating the cGAS-STING pathway blunted the protective effects of iNOS knockout. Moreover, iNOS activated the cGAS-STING pathway in isolated myocytes and this was prevented by depleting cytosolic mtDNA. In addition, disruption of the cGAS-STING pathway suppressed inflammatory cytokine transcription and modulated M1/M2 macrophage polarization, and thus mitigated cardiac remodeling and improved heart function. Finally, increased iNOS expression along with cytosolic mtDNA accumulation and cGAS-STING activation were also seen in human hypertensive hearts. Conclusion: Our findings demonstrate that mtDNA is released into the cytosol and triggers sterile inflammation through the cGAS-STING pathway leading to cardiac dysfunction after pressure overload. iNOS controls mtDNA release and subsequent cGAS activation in pressure-stressed hearts.
| S-EPMC10405855 | biostudies-literature