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Coordinated regulation of immune contexture: crosstalk between STAT3 and immune cells during breast cancer progression.

ABSTRACT: Recent insights into the molecular and cellular mechanisms underlying cancer development have revealed the tumor microenvironment (TME) immune cells to functionally affect the development and progression of breast cancer. However, insufficient evidence of TME immune modulators limit the clinical application of immunotherapy for advanced and metastatic breast cancers. Intercellular STAT3 activation of immune cells plays a central role in breast cancer TME immunosuppression and distant metastasis. Accumulating evidence suggests that targeting STAT3 and/or in combination with radiotherapy may enhance anti-cancer immune responses and rescue the systemic immunologic microenvironment in breast cancer. Indeed, apart from its oncogenic role in tumor cells, the functions of STAT3 in TME of breast cancer involve multiple types of immunosuppression and is associated with tumor cell metastasis. In this review, we summarize the available information on the functions of STAT3-related immune cells in TME of breast cancer, as well as the specific upstream and downstream targets. Additionally, we provide insights about the potential immunosuppression mechanisms of each type of evaluated immune cells. Video abstract.

SUBMITTER: Jin J

PROVIDER: S-EPMC8101191 | biostudies-literature | 2021 May

REPOSITORIES: biostudies-literature

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Coordinated regulation of immune contexture: crosstalk between STAT3 and immune cells during breast cancer progression.

Jin Jing J Li Yi Y Zhao Qijie Q Chen Yue Y Fu Shaozhi S Wu JingBo J

Cell communication and signaling : CCS 20210506 1

Recent insights into the molecular and cellular mechanisms underlying cancer development have revealed the tumor microenvironment (TME) immune cells to functionally affect the development and progression of breast cancer. However, insufficient evidence of TME immune modulators limit the clinical application of immunotherapy for advanced and metastatic breast cancers. Intercellular STAT3 activation of immune cells plays a central role in breast cancer TME immunosuppression and distant metastasis. ...[more]

PMID: 33957948

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Project description:PurposeThe pathogenesis of renal fibrosis (RF) involves intricate interactions between profibrotic processes and immune responses. This study aimed to explore the potential involvement of the pyroptosis signaling pathway in immune microenvironment regulation within the context of RF. Through comprehensive bioinformatics analysis and experimental validation, we investigated the influence of pyroptosis on the immune landscape in RF.MethodsWe obtained RNA-seq datasets from Gene Expression Omnibus (GEO) databases and identified Pyroptosis-Associated Regulators (PARs) through literature reviews. Systematic evaluation of alterations in 27 PARs was performed in RF and normal kidney samples, followed by relevant functional analyses. Unsupervised cluster analysis revealed distinct pyroptosis modification patterns. Using single-sample gene set enrichment analysis (ssGSEA), we examined the correlation between pyroptosis and immune infiltration. Hub regulators were identified via weighted gene coexpression network analysis (WGCNA) and further validated in a single-cell RNA-seq dataset. We also established a unilateral ureteral obstruction-induced RF mouse model to verify the expression of key regulators at the mRNA and protein levels.ResultsOur comprehensive analysis revealed altered expression of 19 PARs in RF samples compared to normal samples. Five hub regulators, namely PYCARD, CASP1, AIM2, NOD2, and CASP9, exhibited potential as biomarkers for RF. Based on these regulators, a classifier capable of distinguishing normal samples from RF samples was developed. Furthermore, we identified correlations between immune features and PARs expression, with PYCARD positively associated with regulatory T cells abundance in fibrotic tissues. Unsupervised clustering of RF samples yielded two distinct subtypes (Subtype A and Subtype B), with Subtype B characterized by active immune responses against RF. Subsequent WGCNA analysis identified PYCARD, CASP1, and NOD2 as hub PARs in the pyroptosis modification patterns. Single-cell level validation confirmed PYCARD expression in myofibroblasts, implicating its significance in the stress response of myofibroblasts to injury. In vivo experimental validation further demonstrated elevated PYCARD expression in RF, accompanied by infiltration of Foxp3+ regulatory T cells.ConclusionsOur findings suggest that pyroptosis plays a pivotal role in orchestrating the immune microenvironment of RF. This study provides valuable insights into the pathogenesis of RF and highlights potential targets for future therapeutic interventions.

Dataset Information

Coordinated regulation of immune contexture: crosstalk between STAT3 and immune cells during breast cancer progression.

Publications

Coordinated regulation of immune contexture: crosstalk between STAT3 and immune cells during breast cancer progression.

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