Oral Squamous Cell Carcinoma Contributes to Differentiation of Monocyte-Derived Tumor-Associated Macrophages via PAI-1 and IL-8 Production

Int J Mol Sci. 2021 Aug 31;22(17):9475. doi: 10.3390/ijms22179475.


Tumor-associated macrophages (TAMs) promote cancer cell proliferation and metastasis, as well as anti-tumor immune suppression. Recent studies have shown that tumors enhance the recruitment and differentiation of TAMs, but the detailed mechanisms have not been clarified. We thus examined the influence of cancer cells on the differentiation of monocytes to TAM subsets, including CD163+, CD204+, and CD206+ cells, in oral squamous cell carcinoma (OSCC) using immunohistochemistry, flow cytometry, and a cytokine array. Furthermore, we investigated the effect of OSCC cells (HSC-2, SQUU-A, and SQUU-B cells) on the differentiation of purified CD14+ cells to TAM subsets. The localization patterns of CD163+, CD204+, and CD206+ in OSCC sections were quite different. The expression of CD206 on CD14+ cells was significantly increased after the co-culture with OSCC cell lines, while the expressions of CD163 and CD204 on CD14+ cells showed no change. High concentrations of plasminogen activator inhibitor-1 (PAI-1) and interleukin-8 (IL-8) were detected in the conditioned medium of OSCC cell lines. PAI-1 and IL-8 stimulated CD14+ cells to express CD206. Moreover, there were positive correlations among the numbers of CD206+, PAI-1+, and IL-8+ cells in OSCC sections. These results suggest that PAI-1 and IL-8 produced by OSCC contribute to the differentiation of monocytes to CD206+ TAMs.

Keywords: CD206; interleukin-8; oral squamous cell carcinoma; plasminogen activator inhibitor–1; tumor-associated macrophage.

MeSH terms

  • Carcinoma, Squamous Cell / pathology
  • Cell Differentiation / genetics
  • Cell Line, Tumor
  • Head and Neck Neoplasms / pathology
  • Humans
  • Immunohistochemistry
  • Interleukin-8 / metabolism
  • Interleukin-8 / physiology
  • Leukocytes, Mononuclear / cytology
  • Macrophages / metabolism*
  • Macrophages / physiology
  • Plasminogen Activator Inhibitor 1 / metabolism
  • Plasminogen Activator Inhibitor 1 / physiology
  • Squamous Cell Carcinoma of Head and Neck / metabolism*
  • Squamous Cell Carcinoma of Head and Neck / pathology
  • Tumor Microenvironment
  • Tumor-Associated Macrophages / metabolism
  • Tumor-Associated Macrophages / physiology


  • CXCL8 protein, human
  • Interleukin-8
  • Plasminogen Activator Inhibitor 1
  • SERPINE1 protein, human