NOTCH1 reverses immune suppression in small cell lung cancer through reactivation of STING [scRNA-seq]
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PROVIDER: PRJNA1026474 | ENA |
REPOSITORIES: ENA
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Project description:NOTCH1 reverses immune suppression in small cell lung cancer through reactivation of STING
| PRJNA1026467 | ENA
Project description:NOTCH1 reverses immune suppression in small cell lung cancer through reactivation of STING [CHIP-seq]
| PRJNA1026473 | ENA
Project description:NOTCH1 reverses immune suppression in small cell lung cancer through reactivation of STING [RNA-seq]
| PRJNA1026472 | ENA
Project description:Downregulation of antigen presentation and lack of immune infiltration are defining features of small cell lung cancer (SCLC) limiting response to immune checkpoint blockade (ICB), While a high MHC Class I, immune-inflamed subset benefits from ICB, underlying mechanisms of immune response in SCLC have yet to be elucidated. Here we show that in the landmark IMpower133 clinical trial high, but not low, NOTCH1 expression is significantly associated with longer survival with the addition of ICB to chemotherapy among ~80% of SCLC patients with neuroendocrine-enriched tumors (ASCL1-enriched, HR 0.39, P=0.0012; NEUROD1-enriched, HR 0.44, P=0.024). Genetic or pharmacologic activation of NOTCH1 in ASCL1 and NEUROD1 SCLC cell lines dramatically up-regulates MHC Class I through epigenetic up-regulation of STING. In syngeneic mouse models, Notch1 activation reprograms SCLC tumors from immune-excluded to immune-inflamed, facilitating durable, complete responses with ICB combined with a STING agonist. STING1 expression is significantly enriched in high compared to low NOTCH1 expressing tumors in IMpower133 thereby validating our proposed mechanism. Our data reveal a previously undiscovered role for NOTCH1 as a critical driver of SCLC immunogenicity and a potential predictive biomarker for ICB in SCLC. NOTCH1 activation may be a therapeutic strategy to unleash anti-tumor immune responses in SCLC and other neuroendocrine cancers in which NOTCH1 is typically suppressed.
2025-06-22 | GSE244946 | GEO
Project description:Downregulation of antigen presentation and lack of immune infiltration are defining features of small cell lung cancer (SCLC) limiting response to immune checkpoint blockade (ICB), While a high MHC Class I, immune-inflamed subset benefits from ICB, underlying mechanisms of immune response in SCLC have yet to be elucidated. Here we show that in the landmark IMpower133 clinical trial high, but not low, NOTCH1 expression is significantly associated with longer survival with the addition of ICB to chemotherapy among ~80% of SCLC patients with neuroendocrine-enriched tumors (ASCL1-enriched, HR 0.39, P=0.0012; NEUROD1-enriched, HR 0.44, P=0.024). Genetic or pharmacologic activation of NOTCH1 in ASCL1 and NEUROD1 SCLC cell lines dramatically up-regulates MHC Class I through epigenetic up-regulation of STING. In syngeneic mouse models, Notch1 activation reprograms SCLC tumors from immune-excluded to immune-inflamed, facilitating durable, complete responses with ICB combined with a STING agonist. STING1 expression is significantly enriched in high compared to low NOTCH1 expressing tumors in IMpower133 thereby validating our proposed mechanism. Our data reveal a previously undiscovered role for NOTCH1 as a critical driver of SCLC immunogenicity and a potential predictive biomarker for ICB in SCLC. NOTCH1 activation may be a therapeutic strategy to unleash anti-tumor immune responses in SCLC and other neuroendocrine cancers in which NOTCH1 is typically suppressed.
2025-06-02 | GSE244945 | GEO
Project description:Downregulation of antigen presentation and lack of immune infiltration are defining features of small cell lung cancer (SCLC) limiting response to immune checkpoint blockade (ICB), While a high MHC Class I, immune-inflamed subset benefits from ICB, underlying mechanisms of immune response in SCLC have yet to be elucidated. Here we show that in the landmark IMpower133 clinical trial high, but not low, NOTCH1 expression is significantly associated with longer survival with the addition of ICB to chemotherapy among ~80% of SCLC patients with neuroendocrine-enriched tumors (ASCL1-enriched, HR 0.39, P=0.0012; NEUROD1-enriched, HR 0.44, P=0.024). Genetic or pharmacologic activation of NOTCH1 in ASCL1 and NEUROD1 SCLC cell lines dramatically up-regulates MHC Class I through epigenetic up-regulation of STING. In syngeneic mouse models, Notch1 activation reprograms SCLC tumors from immune-excluded to immune-inflamed, facilitating durable, complete responses with ICB combined with a STING agonist. STING1 expression is significantly enriched in high compared to low NOTCH1 expressing tumors in IMpower133 thereby validating our proposed mechanism. Our data reveal a previously undiscovered role for NOTCH1 as a critical driver of SCLC immunogenicity and a potential predictive biomarker for ICB in SCLC. NOTCH1 activation may be a therapeutic strategy to unleash anti-tumor immune responses in SCLC and other neuroendocrine cancers in which NOTCH1 is typically suppressed.
2025-06-02 | GSE244944 | GEO
Project description:This SuperSeries is composed of the SubSeries listed below.
2025-06-04 | GSE244947 | GEO
Project description:STING suppresses the reactivation of dormant metastasis
| PRJNA868358 | ENA
Project description:Gammaherpesviruses, including Kaposi’s sarcoma-associated herpesvirus (KSHV) and Epstein-Barr virus (EBV), are DNA viruses that are globally associated with human cancers and establish lifelong latency in the human population. Detection of gammaherpesviral infection by the cGAS-STING innate immune DNA-sensing pathway is critical for suppressing viral reactivation from latency, a process that promotes viral pathogenesis and transmission. We report that Barrier-to-autointegration factor 1 (BAF)-mediated suppression of the cGAS-STING signaling pathway is necessary for reactivation of KSHV and EBV. We demonstrate a novel role for BAF in destabilizing cGAS expression and show that BAF expression in latently infected, reactivating, or uninfected cells leads to suppression of type I interferon-mediated antiviral responses and inhibition of viral replication. Furthermore, BAF overexpression resulted in decreased cGAS expression at the protein level. These results establish BAF as a key regulator of the lifecycle of gammaherpesviruses and a potential target for treating viral infections and malignancies.
2022-12-12 | GSE200781 | GEO
Project description:Metastatic relapse frequently develops from disseminated cancer cells that remain dormant in distant organs after the apparently successful treatment of a primary tumor. Disseminated cancer cells fluctuate between immune evasive quiescent and cell cycle reentry states, which exposes them to elimination by the immune system. Little is known about the molecules that determine immune-mediated clearing of awakened metastatic cells and how this process could be therapeutically activated to eliminate residual disseminated disease in patients. Here, we use models of indolent metastasis to identify cancer cell-intrinsic determinants of immune reactivity during cancer cell exit from dormancy. Through in vivo genetic screens of tumor-intrinsic immune regulators, we identified the STING (stimulator of interferon genes) pathway as a suppressor of metastatic outbreak in dormant models of human and mouse lung adenocarcinoma metastasis. STING levels and signaling activity rise in metastatic progenitors that reenter the cell cycle and are dampened by STING enhancer hypermethylation in breakthrough metastases or enhancer chromatin repression in cells reentering dormancy in response to TGF-β. STING expression in cancer cells from spontaneous metastases suppresses their outgrowth in a NK cell- and CD8+ T cell-dependent manner. Systemic treatment of mice with pharmacologic STING agonists eliminates indolent metastatic cells and prevents spontaneous metastasis, both effects requiring cancer cell STING function. Thus, STING signaling represents a checkpoint against the progression of dormant metastasis and suggests a therapeutically actionable strategy for the prevention of disease relapse. Chromatin immunoprecipitation DNA-sequencing (ChIP-seq) for histone modification markers H3K4me1, H3K4me3, H3K27ac in human lung cancer cells at different stages of metastasis and in cells treated with TGF-β or not.
2023-01-30 | GSE210946 | GEO