Cancer-associated fibroblasts induce monocytic myeloid-derived suppressor cell generation via IL-6/exosomal miR-21-activated STAT3 signaling to promote cisplatin resistance in esophageal squamous cell carcinoma

Zhao, Qitai; Huang, Lan; Qin, Guohui; Qiao, Ying; Ren, Feifei; Shen, Chunyi; Wang, Shumin; Li, Shasha; Lian, Jinyao; Wang, Dan; Yu, Wenbin; Zhang, Yi

doi:10.1016/j.canlet.2021.06.009

Cited by 87 publications

(50 citation statements)

References 59 publications

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“…Pathway analysis also revealed the participation of CAFs in IL-17 signaling pathway, TNF signaling pathway and the innate immune associated pathways. CAFs may shape an immunosuppressive microenvironment through the secretion of CXCL1, IL6 and CCL2 [ 41 – 44 ]. Therefore, we speculated that RNA m 6 A modification CAFs may form the immunosuppressive interaction with tumor cells to promote the progress and metastasis of tumor.…”

Section: Discussionmentioning

confidence: 99%

Single-cell N6-methyladenosine regulator patterns guide intercellular communication of tumor microenvironment that contribute to colorectal cancer progression and immunotherapy

et al. 2022

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Background N6-methyladenosine (m6A) RNA methylation plays a critical role in key genetic events for various cancers; yet, how m6A functions within the tumor microenvironment (TME) remains to be elucidated. Methods A total of 65,362 single cells from single-cell RNA-seq data derived from 33 CRC tumor samples were analyzed by nonnegative matrix factorization (NMF) for 23 m6A RNA methylation regulators. CRC and Immunotherapy cohorts from public repository were used to determine the prognosis and immune response of TME clusters. Results The fibroblasts, macrophages, T and B cells were respectively grouped into 4 to 5 subclusters and then classified according to various biological processes and different marker genes. Furthermore, it revealed that the m6A RNA methylation regulators might be significantly related to the clinical and biological features of CRC, as well as the pseudotime trajectories of main TME cell types. Bulk-seq analysis suggested that these m6A-mediated TME cell subclusters had significant prognostic value for CRC patients and distinguished immune response for patients who underwent ICB therapy, especially for the CAFs and macrophages. Notably, CellChat analysis revealed that RNA m6A methylation-associated cell subtypes of TME cells manifested diverse and extensive interaction with tumor epithelial cells. Further analysis showed that ligand-receptor pairs, including MIF − (CD74 + CXCR4), MIF − (CD74 + CD44), MDK–NCL and LGALS9 − CD45, etc. mediated the communication between m6A associated subtypes of TME cells and tumor epithelial cells. Conclusions Taken together, our study firstly revealed the m6A methylation mediated intercellular communication of the tumor microenvironment in the regulation of tumor growth and antitumor immunomodulatory processes.

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Section: Discussionmentioning

confidence: 99%

Single-cell N6-methyladenosine regulator patterns guide intercellular communication of tumor microenvironment that contribute to colorectal cancer progression and immunotherapy

et al. 2022

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“…CAF-secreted IL6 is also responsible for the generation and activation of MDSCs, which weakens the antitumor immune response and promotes HCC progression ( 60 , 61 ). Recent research in esophageal squamous cell carcinoma demonstrated that CAF-derived exosome-packed microRNA-21 via activating STAT3 signaling promoted the generation of monocyte-MDSCs, thereby causing resistance to cisplatin ( 62 ). Cooperation between MCs and CAFs is an influential microenvironmental driver of prostate cancer progression that results in the transformation of benign epithelial cells into early malignant cells ( 63 ).…”

Section: Discussionmentioning

confidence: 99%

Pan-cancer analyses and molecular subtypes based on the cancer-associated fibroblast landscape and tumor microenvironment infiltration characterization reveal clinical outcome and immunotherapy response in epithelial ovarian cancer

et al. 2022

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BackgroundCancer-associated fibroblasts (CAFs) are essential components of the tumor microenvironment (TME). These cells play a supportive role throughout cancer progression. Their ability to modulate the immune system has also been noted. However, there has been limited investigation of CAFs in the TME of epithelial ovarian cancer (EOC).MethodsWe comprehensively evaluated the CAF landscape and its association with gene alterations, clinical features, prognostic value, and immune cell infiltration at the pan-cancer level using multi-omic data from The Cancer Genome Atlas (TCGA). The CAF contents were characterized by CAF scores based on the expression levels of seven CAF markers using the R package “GSVA.” Next, we identified the molecular subtypes defined by CAF markers and constructed a CAF riskscore system using principal component analysis in the EOC cohort. The correlation between CAF riskscore and TME cell infiltration was investigated. The ability of the CAF riskscore to predict prognosis and immunotherapy response was also examined.ResultsCAF components were involved in multiple immune-related processes, including transforming growth factor (TGF)-β signaling, IL2-STAT signaling, inflammatory responses, and Interleukin (IL) 2-signal transducer and activator of transcription (STAT) signaling. Considering the positive correlation between CAF scores and macrophages, neutrophils, and mast cells, CAFs may exert immunosuppressive effects in both pan-cancer and ovarian cancer cohorts, which may explain accelerated tumor progression and poor outcomes. Notably, two distinct CAF molecular subtypes were defined in the EOC cohort. Low CAF riskscores were characterized by favorable overall survival (OS) and higher efficacy of immunotherapy. Furthermore, 24 key genes were identified in CAF subtypes. These genes were significantly upregulated in EOC and showed a strong correlation with CAF markers.ConclusionsIdentifying CAF subtypes provides insights into EOC heterogeneity. The CAF riskscore system can predict prognosis and select patients who may benefit from immunotherapy. The mechanism of interactions between key genes, CAF markers, and associated cancer-promoting effects needs to be further elucidated.

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“…The miR-21a in exosomes from Lewis lung carcinoma cells accelerates tumor growth through targeting programmed cell death protein 4 (PDCD4) through activating the autocrine production of IL-6 and phosphorylation of the STAT3 signaling pathway and thus enhances the expansion of MDSCs and tumor growth ( 68 ). Furthermore, miR-21 in oral squamous cell carcinoma (OSCC) enhanced the immunosuppressive function of MDSCs through an miR-21/PTEN/PD-L1 axis ( 69 ) and in esophageal squamous cell carcinoma (ESCC), miR-21 activated the STAT3 pathway carried by cancer-associated fibroblast (CAF)-secreting exosomes, which upregulated the induction of M-MDSC corporate with IL-6 ( 70 ). Has-miR-494-3p and has-miR-1260a in pancreatic ductal adenocarcinoma (PDAC)-derived exosomes mediated the suppressive function of MDSCs in an Smad4-dependent way ( 71 ).…”

Section: The Mirnas In the Tumor Microenvironment Regulate Mdscs Func...mentioning

confidence: 99%

Interaction Between microRNAs and Myeloid-Derived Suppressor Cells in Tumor Microenvironment

Liang

et al. 2022

Front. Immunol.

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Myeloid-derived suppressor cells (MDSCs) are a heterogeneous population of cells generated during a series of pathologic conditions including cancer. MicroRNA (miRNA) has been considered as a regulator in different tumor microenvironments. Recent studies have begun to unravel the crosstalk between miRNAs and MDSCs. The knowledge of the effect of both miRNAs and MDSCs in tumor may improve our understanding of the tumor immune escape and metastasis. The miRNAs target cellular signal pathways to promote or inhibit the function of MDSCs. On the other hand, MDSCs transfer bioinformation through exosomes containing miRNAs. In this review, we summarized and discussed the bidirectional regulation between miRNAs and MDSCs in the tumor microenvironment.

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Cancer-associated fibroblasts induce monocytic myeloid-derived suppressor cell generation via IL-6/exosomal miR-21-activated STAT3 signaling to promote cisplatin resistance in esophageal squamous cell carcinoma

Cited by 87 publications

References 59 publications

Single-cell N6-methyladenosine regulator patterns guide intercellular communication of tumor microenvironment that contribute to colorectal cancer progression and immunotherapy

Single-cell N6-methyladenosine regulator patterns guide intercellular communication of tumor microenvironment that contribute to colorectal cancer progression and immunotherapy

Pan-cancer analyses and molecular subtypes based on the cancer-associated fibroblast landscape and tumor microenvironment infiltration characterization reveal clinical outcome and immunotherapy response in epithelial ovarian cancer

Interaction Between microRNAs and Myeloid-Derived Suppressor Cells in Tumor Microenvironment

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