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Anti-inflammatory drugs remodel the tumor immune environment to enhance immune checkpoint blockade efficacy [SZ9]

ABSTRACT: Anti-inflammatory drugs remodel the tumor immune environment to enhance immune checkpoint blockade efficacy [SZ9]

PROVIDER: PRJNA674500 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR12977500.fastq.gz	Fastqsanger.gz
	SRR12977600.fastq.gz	Fastqsanger.gz
	SRR12977501.fastq.gz	Fastqsanger.gz
	SRR12977601.fastq.gz	Fastqsanger.gz
	SRR12977502.fastq.gz	Fastqsanger.gz

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Anti-inflammatory drugs remodel the tumor immune environment to enhance immune checkpoint blockade efficacy

Project description:Anti-inflammatory drugs remodel the tumor immune environment to enhance immune checkpoint blockade efficacy

| PRJNA674502 | ENA

Anti-inflammatory drugs remodel the tumor immune environment to enhance immune checkpoint blockade efficacy [SZ14]

Project description:Anti-inflammatory drugs remodel the tumor immune environment to enhance immune checkpoint blockade efficacy [SZ14]

| PRJNA674507 | ENA

Anti-inflammatory drugs remodel the tumor immune environment to enhance immune checkpoint blockade efficacy [SZ14]

Project description:Identifying strategies to improve the efficacy of immune checkpoint blockade (ICB) remains a major clinical need. Here, we show that therapeutically targeting the COX-2/PGE2/EP2-4 pathway with widely used non-steroidal and steroidal anti-inflammatory drugs synergized with ICB in mouse cancer models. We exploited a bilateral surgery model to harness the heterogeneity in treatment outcome and distinguish responders from non-responders shortly following treatment. Deep cellular and molecular tumor profiling revealed acute IFN-γ-driven tumor remodeling in responder mice that was also associated with patient benefit to ICB. Crucially, monotherapy with COX-2 inhibitors or EP2-4 PGE2 receptor antagonists rapidly induced this response program and, in combination with ICB, increased the intratumoral accumulation of T cells with enhanced effector function. Inhibition of the COX-2/PGE2 pathway in patient-derived tumor fragments from multiple patients and cancer types revealed a similar shift in the tumor inflammatory environment to favor T cell activation. Our findings establish the COX-2/PGE2/EP2-4 axis as an independent immune checkpoint and a readily translatable strategy to switch the tumor inflammatory profile from cold to hot and enhance the efficacy of immunotherapy.

2021-09-13 | GSE160788 | GEO

Anti-inflammatory drugs remodel the tumor immune environment to enhance immune checkpoint blockade efficacy [SZ9]

2021-09-13 | GSE160785 | GEO

Anti-Inflammatory Drugs Remodel the Tumor Immune Environment to Enhance Immune Checkpoint Blockade Efficacy.

Project description:Identifying strategies to improve the efficacy of immune checkpoint blockade (ICB) remains a major clinical need. Here, we show that therapeutically targeting the COX2/PGE2/EP2-4 pathway with widely used nonsteroidal and steroidal anti-inflammatory drugs synergized with ICB in mouse cancer models. We exploited a bilateral surgery model to distinguish responders from nonresponders shortly after treatment and identified acute IFNγ-driven transcriptional remodeling in responder mice, which was also associated with patient benefit to ICB. Monotherapy with COX2 inhibitors or EP2-4 PGE2 receptor antagonists rapidly induced this response program and, in combination with ICB, increased the intratumoral accumulation of effector T cells. Treatment of patient-derived tumor fragments from multiple cancer types revealed a similar shift in the tumor inflammatory environment to favor T-cell activation. Our findings establish the COX2/PGE2/EP2-4 axis as an independent immune checkpoint and a readily translatable strategy to rapidly switch the tumor inflammatory profile from cold to hot. SIGNIFICANCE: Through performing in-depth profiling of mice and human tumors, this study identifies mechanisms by which anti-inflammatory drugs rapidly alter the tumor immune landscape to enhance tumor immunogenicity and responses to immune checkpoint inhibitors.See related commentary by Melero et al., p. 2372.This article is highlighted in the In This Issue feature, p. 2355.

| S-EPMC7611767 | biostudies-literature

Anti-inflammatory drugs remodel the tumor immune environment to enhance immune checkpoint blockade efficacy

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

2021-09-13 | GSE160789 | GEO

Leveraging CD16 fusion receptors to remodel the immune response for enhancing iPSC-derived NK cell anti-tumor immunotherapy

Project description:We developed a novel hnCD16FR construct that exhibit more potent cytotoxicity than reported hnCD16, which is a promising approach to treating hematologic malignancies and solid tumors with improved ADCC properties. We also offer a rationale for NK activation domains that remodel immune response to enhance CD16 signaling in NK cells.

2023-06-21 | GSE223656 | GEO

The polymethoxyflavone Sudachitin modulates the circadian clock to enhance energy metabolism and remodel liver physiology

Project description:The polymethoxyflavone Sudachitin modulates the circadian clock to enhance energy metabolism and remodel liver physiology

| PRJNA871200 | ENA

Identification of drugs that enhance skin repair using dermal stem cell-based screens [Rat]

Project description:Here, we asked whether we could identify pharmacological agents that enhance endogenous stem cell function to promote skin repair, focusing on SKPs (skin-derived precursors) a dermal precursor cell population. Libraries of compounds already used in humans were screened for their ability to enhance the self-renewal of human and rodent SKPs. We identified and validated 5 such compounds, and showed that two of them, alprostadil and trimebutine maleate, enhanced the repair of full thickness skin wounds in middle-aged mice. Moreover, SKPs isolated from drug-treated skin displayed long-term increases in self-renewal when cultured in basal growth medium without drugs. Both alprostadil and trimebutine maleate likely mediated increases in SKPs self-renewal by moderate hyperactivation of the MEK-ERK pathway. These findings identify candidates for potential clinical use in human skin repair, and provide support for the idea that pharmacological activation of endogenous tissue precursors represents a viable therapeutic strategy. We obtained three independent isolates of SKPs from newborn Sprague-Dawley rat pups. Secondary SKPs spheres were dissociated, treated with 100 nM of alprostadil, trimebutine maleate or 100 nM of both trimebutine maleate and trametinib for 24 hour. RNA samples deriving from these cells were analyzed on the Affymetrix GeneChip Rat Gene 2.0 ST Array.

2015-12-24 | E-GEOD-73328 | biostudies-arrayexpress

Tumour mtDNA mutations drive aerobic glycolysis to enhance checkpoint blockade

Project description:Mitochondrial DNA (mtDNA) encodes essential machinery for respiration and metabolic homeostasis but is paradoxically among the most common targets of somatic mutations in the cancer genome, with truncating mutations in complex I genes being over-represented1 . While mtDNA mutations have been associated with both improved and worsened prognoses in several cancer lineages1–3, whether these mutations are drivers, or exert any functional effect on tumour biology remains controversial. Here we discover that complex I-encoding mtDNA mutations are sufficient to remodel the tumour immune landscape and therapeutic resistance to immune checkpoint blockade. Using mtDNA base editing technology we engineered recurrent truncating mutations in the mtDNA-encoded complex I gene, Mt-Nd5, into murine models of melanoma. Mechanistically, these mutations promoted utilisation of pyruvate as a terminal electron acceptor and increased glycolytic flux driven by an over-reduced NAD pool and NADH shuttling between GAPDH and MDH1, mediating a Warburg-like metabolic shift. In turn, without modifying tumour growth, this altered cancer cell-intrinsic metabolism reshaped the tumour microenvironment of mouse and human cancer in a mutation load-dependent fashion, encouraging an anti-tumour immune response. This subsequently sensitises both mouse and human cancers with high mtDNA mutant heteroplasmy to immune checkpoint blockade. Strikingly, patient lesions bearing >50% mtDNA mutation load demonstrated a >2.5-fold improved response rate to checkpoint inhibitor blockade. Taken together these data nominate mtDNA mutations as functional regulators of cancer metabolism and tumour biology, with potential for therapeutic exploitation and treatment stratification.

2023-11-08 | PXD039705 | Pride

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