CD206⁺ tumor-associated macrophages promote proliferation and invasion in oral squamous cell carcinoma via EGF production

Tumor-associated macrophages (TAMs) promote tumor progression and inhibit anti-tumor immune response by producing various mediators and preferentially express CD163, CD204, and CD206. However, the role of these TAM subsets in oral squamous cell carcinoma (OSCC) remains unclear. Here we investigated the expression and function of TAM subsets in OSCC, especially in cancer cell proliferation. Biopsy sample from 44 patients with OSCC were examined for the expression of TAM markers and EGF by immunohistochemistry. EGF production of TAM subsets isolated from OSCC patients was assessed by flow cytometry. We also examined the effect of conditioned medium from TAM subsets on the proliferation of OSCC cells. CD163⁺ cells were detected diffusely all over the tumor and connective tissue area, while CD204⁺ and CD206⁺ cells were mainly detected in/around the tumors. Flow cytometric analysis found that CD206⁺ TAMs strongly produced EGF compared with CD163⁺ and CD204⁺ TAMs. Cell proliferation and invasion of OSCC cells cultured with conditioned medium of CD206⁺ TAMs were strongly enhanced and inhibited by anti-EGFR. The number of CD206⁺ TAMs positively correlated with worse clinical prognosis. Our results revealed differences in localization and EGF production among these TAM subsets. CD206⁺ TAMs might play a critical role in the proliferation of OSCC via EGF production.