OSCC cell-secreted exosomal CMTM6 induced M2-like macrophages polarization via ERK1/2 signaling pathway
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ORIGINAL ARTICLE
OSCC cell‑secreted exosomal CMTM6 induced M2‑like macrophages polarization via ERK1/2 signaling pathway Xin Pang1 · Sha‑sha Wang1 · Mei Zhang1 · Jian Jiang2 · Hua‑yang Fan1 · Jia‑shun Wu1 · Hao‑fan Wang1 · Xin‑hua Liang1 · Ya‑ling Tang1 Received: 24 April 2020 / Accepted: 12 October 2020 © Springer-Verlag GmbH Germany, part of Springer Nature 2020
Abstract Background CKLF-like MARVEL transmembrane domain-containing 6 (CMTM6) is a critical regulator of tumor immunology among various cancers. However, the role and underlying molecular mechanism of CMTM6 in oral squamous cell carcinoma (OSCC) progression remains unclear. Methods The expression of CMTM6, PD-L1 and CD163 in OSCC tissues were detected by immunohistochemistry on tissue microarray. The effect of CMTM6 knockdown on OSCC cells and macrophage polarization were analyzed by CCK-8 assay, apoptotic assay, would-healing assay, transwell assay and qPCR. OSCC cell derived exosomes were obtained by ultracentrifugation and the mechanistic studies were conducted by qPCR and Western Blot. 4-Nitroquinoline N-oxide (4NQO) induced OSCC mice were used for verifying the effect of CMTM6 downregulation on M2 macrophage infiltration and tumor growth. Results In OSCC samples, higher CMTM6 expression has been obviously associated with higher pathological stage of OSCC patients, CD163 + macrophages infiltration and PD-L1 expression. CMTM6 knockdown of OSCC cells inhibited proliferative, migrative and invasive abilities of OSCC cells, as well as inhibited M2 macrophage polarization in vitro with downregulating PD-L1 expression. Importantly, exosomes from OSCC cells shuttled CMTM6 to macrophages and promoted M2-like macrophage polarization through activating ERK1/2 signaling. In addition, in 4NQO-induced OSCC mice, CMTM6 level was positively associated with CD163, CD206 and PD-L1 as well as M2-like macrophage infiltration. Conclusion OSCC cell-secreted exosomal CMTM6 induces M2-like macrophages polarization to promote malignant progression via ERK1/2 signaling pathway, revealing a novel crosstalk between cancer cells and immune cells in OSCC microenvironment. Keywords Oral squamous cell carcinoma · CKLF-like MARVEL transmembrane domain-containing 6 · Macrophage · Exosome · PD-L1
Xin Pang, Sha-sha Wang and Mei Zhang contributed equally to this work. * Xin‑hua Liang [email protected] * Ya‑ling Tang [email protected] 1
State Key Laboratory of Oral Diseases and National Clinical Research Center for Oral Diseases and Department of Oral and Maxillofacial Surgery, Hospital of Stomatology, Sichuan University, No.14, Sec. 3, Renminnan Road, Chengdu 610041, West China, China
Department of Head and Neck Surgery, Sichuan Cancer Center, School of Medicine, Sichuan Cancer Hospital and Institute, University of Electronic Science and Technology of China, Chengdu, Sichuan, China
2
Introduction Oral squamous cell carcinoma (OSCC) is the most common malignancy of oral cancers, and results in more than 145 thousand mortality annually overworld [1]. Traditional
