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NOTCH1 reverses innate immune suppression in small cell lung cancer.

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Mus musculus Homo sapiens

PROVIDER: GSE244947 | GEO | 2025/06/04

REPOSITORIES: GEO

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NOTCH1 reverses innate immune suppression in small cell lung cancer [CHIP-seq]

Project description:Suppression of antigen presentation is a mechanism employed by cancers, such small cell lung cancer (SCLC), to avoid immune surveillance and resist response to immune checkpoint blockade (ICB). A subset of SCLC with decreased neuroendocrine (NE) features have increased antigen presentation and prolonged survival with ICB but the underlying mechanism(s) are unclear and no biomarkers for patient selection are available in the SCLC clinic. Here, we discover that NOTCH1 is a key driver of intrinsic tumor immunity and anti-tumor immune response in SCLC. Mechanistically, NOTCH1-mediated NE to non-NE transdifferentiation reverses innate immune suppression and upregulates MHC Class I through epigenetic re-expression of STING and increased STING pathway sensitivity through DNA damage and release of cytosolic DNA. STING agonism synergizes with anti-PD-L1 therapy to mediate tumor eradication in a Notch-transdifferentiated syngeneic SCLC mouse model. Our results implicate Notch pathway downregulation as a mechanism of immunoevasion that may be therapeutically targeted to augment anti-tumor immune response.

2025-06-02 | GSE244944 | GEO

NOTCH1 reverses innate immune suppression in small cell lung cancer [RNA-seq]

2025-06-02 | GSE244945 | GEO

NOTCH1 reverses immune suppression in small cell lung cancer through reactivation of STING

Project description:NOTCH1 reverses immune suppression in small cell lung cancer through reactivation of STING

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NOTCH1 reverses immune suppression in small cell lung cancer through reactivation of STING [RNA-seq]

Project description:NOTCH1 reverses immune suppression in small cell lung cancer through reactivation of STING [RNA-seq]

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NOTCH1 reverses immune suppression in small cell lung cancer through reactivation of STING [CHIP-seq]

Project description:NOTCH1 reverses immune suppression in small cell lung cancer through reactivation of STING [CHIP-seq]

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NOTCH1 reverses immune suppression in small cell lung cancer through reactivation of STING [scRNA-seq]

Project description:NOTCH1 reverses immune suppression in small cell lung cancer through reactivation of STING [scRNA-seq]

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Targeting TREX1 Induces Innate Immune Response in Drug-Resistant Small-Cell Lung Cancer.

Project description:Small-cell lung cancer (SCLC) is the most lethal type of lung cancer. Paradoxically, this tumor displays an initial exquisite response to chemotherapy; however, at relapse, the tumor is highly resistant to subsequent available therapies. Here, we report that the expression of three prime repair exonuclease 1 (TREX1) is strongly induced in chemoresistant SCLCs. Assay for transposase-accessible chromatin using sequencing and chromatin immunoprecipitation sequencing revealed a significant increase in chromatin accessibility and transcriptional activity of TREX1 gene locus in chemoresistant SCLCs. Analyses of human SCLC tumors and patient-derived xenografts (PDX) also showed an increase in TREX1 expression in postchemotherapy samples. TREX1 depletion caused the activation of cyclic GMP-AMP synthase stimulator of interferon gene pathway due to cytoplasmic accumulation of damage-associated double-stranded DNA, inducing immunogenicity and enhancing the sensitivity of drug-resistant cells to chemotherapy. These findings suggest TREX1 upregulation may partially contribute to the survival of resistant cells, and its inhibition may represent a promising therapeutic strategy to enhance antitumor immunity and potentiate the efficacy of chemotherapy and/or immunotherapy in chemoresistant SCLCs. Significance: In this study, we show that targeting TREX1 induces an innate immune response and resensitizes SCLC cells to chemotherapy, representing a promising novel target for "immunologically" cold tumors, such as SCLC.

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LXR/ApoE Activation Restricts Innate Immune Suppression in Cancer.

Project description:Therapeutic harnessing of adaptive immunity via checkpoint inhibition has transformed the treatment of many cancers. Despite unprecedented long-term responses, most patients do not respond to these therapies. Immunotherapy non-responders often harbor high levels of circulating myeloid-derived suppressor cells (MDSCs)-an immunosuppressive innate cell population. Through genetic and pharmacological approaches, we uncovered a pathway governing MDSC abundance in multiple cancer types. Therapeutic liver-X nuclear receptor (LXR) agonism reduced MDSC abundance in murine models and in patients treated in a first-in-human dose escalation phase 1 trial. MDSC depletion was associated with activation of cytotoxic T lymphocyte (CTL) responses in mice and patients. The LXR transcriptional target ApoE mediated these effects in mice, where LXR/ApoE activation therapy elicited robust anti-tumor responses and also enhanced T cell activation during various immune-based therapies. We implicate the LXR/ApoE axis in the regulation of innate immune suppression and as a target for enhancing the efficacy of cancer immunotherapy in patients.

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Small cell lung cancer

Project description:This SuperSeries is composed of the SubSeries listed below.

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