Cancer Immunol Immunother. 2021 Apr;70(4):1015-1029.doi:10.1007/s00262-020-02741-2. Epub 2020 Oct 26.

OSCC cell-secreted exosomal CMTM6 induced M2-like macrophages polarization via ERK1/2 signaling pathway

Xin Pang #  1 Sha-Sha Wang #  1 Mei Zhang #  1 Jian Jiang  2 Hua-Yang Fan  1 Jia-Shun Wu  1 Hao-Fan Wang  1 Xin-Hua Liang  3 Ya-Ling Tang  4 Affiliations


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: CKLF-like MARVEL transmembrane domain-containing 6; Exosome; Macrophage; Oral squamous cell carcinoma; PD-L1.