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  2. 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

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

  • Cancer Lett. 2021 Oct 10;518:35-48. doi: 10.1016/j.canlet.2021.06.009.
Qitai Zhao 1 Lan Huang 1 Guohui Qin 1 Yamin Qiao 1 Feifei Ren 1 Chunyi Shen 1 Shumin Wang 1 Shasha Liu 1 Jinyao Lian 1 Dan Wang 1 Weina Yu 1 Yi Zhang 2
Affiliations

Affiliations

  • 1 Biotherapy Center and Cancer Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, Henan, China; State Key Laboratory of Esophageal Cancer Prevention & Treatment, Zhengzhou, 450052, Henan, China; Henan Key Laboratory for Tumor Immunology and Biotherapy, Zhengzhou, 450052, China.
  • 2 Biotherapy Center and Cancer Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, Henan, China; State Key Laboratory of Esophageal Cancer Prevention & Treatment, Zhengzhou, 450052, Henan, China; School of Life Sciences, Zhengzhou University, Zhengzhou, 450052, Henan, China; Henan Key Laboratory for Tumor Immunology and Biotherapy, Zhengzhou, 450052, China. Electronic address: yizhang@zzu.edu.cn.
Abstract

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.

Keywords

Cancer-associated fibroblasts; Cisplatin resistance; Esophageal squamous cell carcinoma; Monocytic myeloid-derived suppressor cells; Signal transducing activator of transcription 3.

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