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Targeting IRE1α reprograms the tumor microenvironment and enhances anti-tumor immunity in prostate cancer [scRNA-seq2]

ABSTRACT: Targeting IRE1α reprograms the tumor microenvironment and enhances anti-tumor immunity in prostate cancer [scRNA-seq2]

PROVIDER: PRJNA1141962 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR30167496_1.fastq.gz	Fastqsanger.gz
	SRR30167496_2.fastq.gz	Fastqsanger.gz
	SRR30167497_1.fastq.gz	Fastqsanger.gz
	SRR30167497_2.fastq.gz	Fastqsanger.gz
	SRR30167498_1.fastq.gz	Fastqsanger.gz

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Targeting IRE1α reprograms the tumor microenvironment and enhances anti-tumor immunity in prostate cancer [scRNA-seq2]

Project description:Unfolded protein response (UPR) is a central intracellular stress response pathway that is hijacked by tumor cells for their survival. However, how activation of UPR in cancer cells may shape the tumor microenvironment (TME) remains largely unexplored. Here, we investigated the potential role of IRE1α signaling on modulation of TME dynamics in prostate cancer (PCa). We found that IRE1α is increased in PCa patient tumors and genetic inhibition of IRE1α in syngeneic mouse PCa models, as well as in an orthotopic model, dramatically reduced tumor growth. Multiomics analysis suggested that IRE1α ablation in cancer cells significantly potentiated interferon (IFN) response and activation of immune system related pathways in the TME. Single-cell RNA-sequencing (scRNA-seq) revealed that the abundance of immunosuppressive cells, such as tumor-associated macrophages (TAMs), were markedly reduced in the IRE1α deficient tumors. Geneset Enrichment Analysis demonstrated that IFN response was significantly enriched in TAMs, cancer cells, and dendritic cells. Notably, the small molecule IRE1α inhibitor MKC8866 (ORIN1001), currently in clinical trials, reprogrammed the TME and enhanced the response to anti-PD-1 blockade therapy in syngeneic PCa mouse models. Furthermore, a novel scRNA-seq-derived TAM gene signature is strongly associated with poor PCa survival, which is reduced by the MKC8866 + anti-PD-1 combination therapy. Our findings indicate that activation of IRE1α signaling not only promotes cancer cell growth and survival, but it also interferes with anti-tumor immunity in the TME. Thus, IRE1α targeting could present a novel approach for improving anti-PD-1 immunotherapy in PCa.

2024-08-29 | GSE273458 | GEO

Targeting IRE1α reprograms the tumor microenvironment and enhances anti-tumor immunity in prostate cancer [RNA-Seq]

2024-08-29 | GSE240371 | GEO

Targeting IRE1α reprograms the tumor microenvironment and enhances anti-tumor immunity in prostate cancer [scRNA-seq]

2024-11-22 | GSE240382 | GEO

Targeting IRE1α reprograms the tumor microenvironment and enhances anti-tumor immunity in prostate cancer

Project description:Targeting IRE1α reprograms the tumor microenvironment and enhances anti-tumor immunity in prostate cancer

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Targeting IRE1α reprograms the tumor microenvironment and enhances anti-tumor immunity in prostate cancer [RNA-Seq]

Project description:Targeting IRE1α reprograms the tumor microenvironment and enhances anti-tumor immunity in prostate cancer [RNA-Seq]

| PRJNA1003455 | ENA

Targeting IRE1α reprograms the tumor microenvironment and enhances anti-tumor immunity in prostate cancer [scRNA-seq]

Project description:Targeting IRE1α reprograms the tumor microenvironment and enhances anti-tumor immunity in prostate cancer [scRNA-seq]

| PRJNA1003475 | ENA

Targeting IRE1α reprograms the tumor microenvironment and enhances anti-tumor immunity in prostate cancer

Project description:Unfolded protein response (UPR) is a central stress response pathway in normal cells that is hijacked by tumor cells for their survival. However, how activation of UPR in cancer cells shapes the tumor microenvironment (TME) remain largely unexplored. Here, we investigated the role of IRE1Î±-XBP1s on modulation of TME dynamics in prostate cancer (PCa).

2024-08-28 | PXD044287 | Pride

Targeting IRE1α reprograms the tumor microenvironment and enhances anti-tumor immunity in prostate cancer

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

2024-08-29 | GSE240383 | GEO

Non-canonical activation of IRE1α during Candida albicans infection enhances macrophage fungicidal activity

Project description:Infection by intracellular pathogens can trigger activation of the IRE1α branch of the unfolded protein response (UPR), which then modulates innate immunity and infection outcomes during bacterial or viral infection. However, the mechanisms by which infection activates IRE1α have not been fully elucidated. While recognition of microbe-associated molecular patterns can activate IRE1α, it is unclear whether the canonical role of IRE1α in detecting misfolded proteins is required for its activation. Here, we report that Candida albicans infection of macrophages results in IRE1α activation through C-type lectin receptor signaling, reinforcing a role for IRE1α as a central regulator of host responses to infection by a broad range of pathogens. However, IRE1α activation was not preceded by protein misfolding in response to either C. albicans infection or lipopolysaccharide treatment, implicating a non-canonical mode of IRE1α activation after recognition of microbial patterns. Investigation of the phenotypic consequences of IRE1α activation in macrophage antimicrobial responses revealed that IRE1α activity enhances the fungicidal activity of macrophages. Macrophages lacking IRE1α activity displayed inefficient phagolysosomal fusion, enabling C. albicans to evade fungal killing and escape the phagosome. Together, these data provide mechanistic insight for the non-canonical activation of IRE1α during infection, and reveal central roles for IRE1α in macrophage antifungal responses.

2023-11-13 | GSE244303 | GEO

Tumor-intrinsic IRE1α signaling controls protective immunity in lung cancer.

Project description:The IRE1α-XBP1 arm of the unfolded protein response (UPR) has emerged as a central orchestrator of malignant progression and immunosuppression in various cancer types. Yet the role of this pathway in non-small cell lung cancer (NSCLC) has remained largely unexplored. Using an RNA-seq based computational XBP1s detection method applied to TCGA datasets, we uncovered that expression of the IRE1a-generated XBP1s mRNA isoform predicts poor survival in NSCLC patients. Ablation of IRE1a in malignant cells delayed tumor progression and extended survival in an XBP1-dependent fashion in mouse models of NSCLC. This protective effect was accompanied by marked alterations in both lymphoid and myeloid intratumoral cell subsets that elicited durable adaptive anti-cancer immunity. Mechanistically, cancer cell-intrinsic IRE1α activation sustained mPGES-1 expression, enabling production of the immunosuppressive lipid mediator PGE2 in the tumor microenvironment (TME). Accordingly, restoring mPGES-1 expression in IRE1αKO cancer cells rescued normal tumor progression. By identifying the dominant transcriptional networks controlled by IRE1α in mouse lung tumors, we further developed a new gene signature that predicted immune cell infiltration and overall survival in human NSCLC. Hence, our study unveils a key immunoregulatory role for cancer cell-intrinsic IRE1α activation and suggests that targeting this pathway may help enhance anti-tumor immunity in NSCLC.

2022-05-13 | GSE202939 | GEO

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