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

• DOI: 10.1016/j.canlet.2021.06.009
• Publication Date: 2021-06-15T22:25:36Z
• Authors: Qitai Zhao; Lan Huang; Guohui Qin; Yamin Qiao; Feifei Ren; Chunyi Shen; Shumin Wang; Shasha Liu; Jinyao Lian; Dan Wang; Weina Yu; Yi Zhang
• Keywords: Myeloid-derived Suppressor Cell

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.