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

• Published in: Cancer Immunology, Immunotherapy Vol. 70; no. 4; pp. 1015 - 1029
• Main Authors: Pang, Xin, Wang, Sha-sha, Zhang, Mei, Jiang, Jian, Fan, Hua-yang, Wu, Jia-shun, Wang, Hao-fan, Liang, Xin-hua, Tang, Ya-ling
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Springer Berlin Heidelberg 01.04.2021; Springer Nature B.V
• Subjects: Animals; Apoptosis; Biomarkers, Tumor - genetics; Biomarkers, Tumor - metabolism; Cancer Research; CD163 antigen; Cell Movement; Cell Proliferation; Cholecystokinin; Exosomes; Exosomes - genetics; Exosomes - metabolism; Extracellular signal-regulated kinase; Female; Gene Expression Regulation, Neoplastic; Humans; Immunohistochemistry; Immunology; Infiltration; Invasiveness; Kinases; Macrophage Activation - immunology; Macrophages; MARVEL Domain-Containing Proteins - genetics; MARVEL Domain-Containing Proteins - metabolism; Medicine; Medicine & Public Health; Metastases; Mice; Mice, Inbred C57BL; Microenvironments; Mitogen-Activated Protein Kinase 1 - genetics; Mitogen-Activated Protein Kinase 1 - metabolism; Mitogen-Activated Protein Kinase 3 - genetics; Mitogen-Activated Protein Kinase 3 - metabolism; Mouth Neoplasms - immunology; Mouth Neoplasms - metabolism; Mouth Neoplasms - pathology; Myelin Proteins - genetics; Myelin Proteins - metabolism; Oncology; Oral cancer; Oral squamous cell carcinoma; Original; Original Article; PD-L1 protein; Polarization; Prognosis; Signal transduction; Squamous cell carcinoma; Squamous Cell Carcinoma of Head and Neck - immunology; Squamous Cell Carcinoma of Head and Neck - metabolism; Squamous Cell Carcinoma of Head and Neck - pathology; Tumor Cells, Cultured; Tumor Microenvironment; Ultracentrifugation; Xenograft Model Antitumor Assays; Exosome; Oral squamous cell carcinoma; Macrophage; PD-L1; CKLF-like MARVEL transmembrane domain-containing 6
• ISSN: 0340-7004; 1432-0851
• DOI: 10.1007/s00262-020-02741-2

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.