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

• Published in: Cancer letters Vol. 518; pp. 35 - 48
• Main Authors: Zhao, Qitai, Huang, Lan, Qin, Guohui, Qiao, Yamin, Ren, Feifei, Shen, Chunyi, Wang, Shumin, Liu, Shasha, Lian, Jinyao, Wang, Dan, Yu, Weina, Zhang, Yi
• Format: Journal Article
• Language: English
• Published: Ireland Elsevier B.V 10.10.2021; Elsevier Limited
• Subjects: Apoptosis; Autocrine signalling; Cancer-associated fibroblasts; Cancer-Associated Fibroblasts - metabolism; Cancer-Associated Fibroblasts - pathology; CD11b antigen; Cell Differentiation - physiology; Cell Line; Cell Line, Tumor; Chemotherapy; Cisplatin; Cisplatin - pharmacology; Cisplatin resistance; Drug resistance; Drug Resistance, Neoplasm - physiology; Esophageal cancer; Esophageal Neoplasms - drug therapy; Esophageal Neoplasms - metabolism; Esophageal Neoplasms - pathology; Esophageal squamous cell carcinoma; Esophageal Squamous Cell Carcinoma - drug therapy; Esophageal Squamous Cell Carcinoma - metabolism; Esophageal Squamous Cell Carcinoma - pathology; Esophagus; Ethics; Exosomes - metabolism; Exosomes - pathology; Extracellular matrix; Fibroblasts; Flow cytometry; Growth factors; Humans; Interleukin 6; Interleukin 6 receptors; Interleukin-6 - metabolism; Lymphocytes; Medical prognosis; Metastases; Metastasis; MicroRNAs; MicroRNAs - metabolism; miRNA; Monocytes; Monocytes - metabolism; Monocytes - pathology; Monocytic myeloid-derived suppressor cells; Myeloid cells; Myeloid Cells - metabolism; Myeloid Cells - pathology; Myeloid-Derived Suppressor Cells - metabolism; Myeloid-Derived Suppressor Cells - pathology; Paracrine signalling; Patients; Proteins; Signal transducing activator of transcription 3; Signal Transduction - physiology; Squamous cell carcinoma; Stat3 protein; STAT3 Transcription Factor - metabolism; Stromal cells; Suppressor cells; Transcription; Tumor cells; Tumors; Beijing China; United States > US; China; Cancer-associated fibroblasts; Esophageal squamous cell carcinoma; Signal transducing activator of transcription 3; Cisplatin resistance; Monocytic myeloid-derived suppressor cells
• ISSN: 0304-3835; 1872-7980; 1872-7980
• DOI: 10.1016/j.canlet.2021.06.009

Drug resistance remains the major obstacle limiting the effectiveness of chemotherapy for esophageal squamous cell carcinoma (ESCC)[1]. However, how stromal cells cooperate with immune cells to contribute to drug resistance is not yet fully understood. In this study, we observed that monocytic myeloid-derived suppressor cells (M-MDSCs) were correlated with cisplatin resistance in patients with ESCC. Furthermore, CAFs promoted differentiation of monocytes into M-MDSCs phenotypically and functionally in vitro. Mechanically, both interleukin (IL)-6 and exosome-packed microRNA-21 (miR-21) secreted by CAFs synergistically promoted the generation of M-MDSCs via activating the signal transducing activator of transcription 3 (STAT3) by IL-6 in an autocrine manner. Combined blocking of IL-6 receptor and inhibition of miR-21 significantly reversed CAF-mediated M-MDSC generation. Notably, the effects of CAFs on M-MDSC induction were abolished by inhibiting STAT3 signaling. Functionally, CAF-induced M-MDSCs promoted drug resistance of tumor cells upon cisplatin treatment. Clinically, ESCC patients with high infiltration of CAFs and CD11b+ myeloid cells had unfavorable predicted overall survival both in our cohort and in TCGA data. Taken together, our study reveals a paracrine and autocrine of IL-6 caused by CAFs co-activate STAT3 signaling, promoting the generation of M-MDSCs, and highlights the important role of CAFs in cooperation with M-MDSCs in promoting drug resistance, thus providing potential opportunities for reversing drug resistance through inhibition of STAT3 signaling. •Cancer-associated fibroblasts(CAFs) promoted M-MDSCs generation through activating STAT3 signaling by IL-6 in paracrine and exosomal-miR-21 medicated of autocrine in monocytes.•Monocytic myeloid-derived suppressor cells (M-MDSCs) mediated cisplatin resistance of esophageal squamous cell carcinoma(ESCC).•Co-infiltration of M-MDSCs and CAFs predict a poor survival of ESCC in our clinical cohort and TCGA dataset.