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

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A Correction to this article was published on 25 November 2021

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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.

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Acknowledgements

This work was supported by National Natural Science Foundation of China grants (Nos.8207300, 81672672, 81972542 and 81902779) and National Science Foundation of Sichuan Province (Nos.2020JDRC0018 and 2020YFS0171).

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Author notes

  1. Xin Pang, Sha-sha Wang and Mei Zhang contributed equally to this work.

Authors and Affiliations

  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

    Xin Pang, Sha-sha Wang, Mei Zhang, Hua-yang Fan, Jia-shun Wu, Hao-fan Wang, Xin-hua Liang & Ya-ling Tang

  2. 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

    Jian Jiang

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Contributions

Xin Pang, Sha-sha Wang and Mei Zhang performed most of the experiments and wrote the manuscript. Hua-yang Fan and Jia-shun Wu performed the mice materials. Hao-fan Wang analyzed data and assisted in manuscript writing. Xin-hua Liang and Ya-ling Tang conceived the study and performed the final corrections.

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Correspondence to Xin-hua Liang or Ya-ling Tang.

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Pang, X., Wang, Ss., Zhang, M. et al. OSCC cell-secreted exosomal CMTM6 induced M2-like macrophages polarization via ERK1/2 signaling pathway. Cancer Immunol Immunother 70, 1015–1029 (2021). https://doi.org/10.1007/s00262-020-02741-2

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