Targeting CMTM6 Suppresses Stem Cell-Like Properties and Enhances Antitumor Immunity in Head and Neck Squamous Cell Carcinoma

Cancer Immunol Res. 2020 Feb;8(2):179-191. doi: 10.1158/2326-6066.CIR-19-0394. Epub 2019 Nov 26.


CMTM6, a regulator of PD-L1 expression, also modulates tumor immunity. Little is known about the function of CMTM6 and its mechanism of action in head and neck squamous cell carcinoma (HNSCC). In this study, we found by IHC analysis that CMTM6 overexpression predicted a poor prognosis for patients with HNSCC. We discovered that CMTM6 expression was correlated with increased activity through the Wnt/β-catenin signaling pathway, which is essential for tumorigenesis, maintenance of cancer stem cells (CSC), and the epithelial-to-mesenchymal transition (EMT) characteristic of multiple cancers. We used short hairpin RNA to eliminate expression of CMTM6, which led, in HNSCC cells, to reduced expression of nuclear β-catenin as well as inhibition of stem cell-like properties, TGFβ-induced EMT, and cell proliferation. Consistent with these results, we identified a significant positive correlation between expression of CMTM6 and EMT- and CSC-related genes in The Cancer Genome Atlas (TCGA). We found positive correlations for both RNA and protein between expression of CMTM6 and immune checkpoint components. CMTM6 silencing-induced PD-L1 downregulation delayed SCC7 tumor growth and increased CD8+ and CD4+ T-cell infiltration. The proportions of PD-1+, TIM-3+, VISTA+, LAG-3+, and B7-H3+ exhausted T cells were decreased significantly in the CMTM6 knockdown group. CMTM6 thus regulates stemness, EMT, and T-cell dysfunction and may be a promising therapeutic target in the treatment of HNSCC.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • B7-H1 Antigen / immunology
  • B7-H1 Antigen / metabolism
  • Carcinogenesis / genetics
  • Carcinogenesis / immunology
  • Carcinogenesis / metabolism
  • Cell Line, Tumor
  • Cell Proliferation
  • Disease Models, Animal
  • Epithelial-Mesenchymal Transition
  • Female
  • Gene Knockout Techniques
  • Head and Neck Neoplasms / immunology*
  • Head and Neck Neoplasms / metabolism
  • Head and Neck Neoplasms / pathology
  • Humans
  • Immunity, Cellular / immunology
  • MARVEL Domain-Containing Proteins
  • Membrane Proteins / antagonists & inhibitors*
  • Membrane Proteins / genetics
  • Membrane Proteins / immunology
  • Membrane Proteins / metabolism
  • Mice
  • Mice, Inbred C3H
  • Myelin Proteins
  • Neoplasm Grading
  • Neoplastic Stem Cells / immunology*
  • Neoplastic Stem Cells / metabolism
  • Squamous Cell Carcinoma of Head and Neck / immunology*
  • Squamous Cell Carcinoma of Head and Neck / metabolism
  • Squamous Cell Carcinoma of Head and Neck / pathology
  • Survival Rate
  • Wnt Signaling Pathway


  • B7-H1 Antigen
  • CD274 protein, human
  • CMTM6 protein, human
  • MARVEL Domain-Containing Proteins
  • Membrane Proteins
  • Myelin Proteins