Oral squamous cell carcinoma cell-derived GM-CSF regulates PD-L1 expression in tumor-associated macrophages through the JAK2/STAT3 signaling pathway

Previous study reported that gastric cancer-derived granulocyte-macrophage colony-stimulating factor (GM-CSF) could mediate neutrophil activation and induce PD-L1 expression through JAK2/STAT3 signaling pathway. Moreover, this pathway in various cancers could also regulate PD-L1 expression of tumor cells. Therefore, our study aimed to investigate whether the JAK2/STAT3 pathway regulates PD-L1 expression in tumor-associated macrophages (TAMs) in oral squamous cell carcinoma (OSCC), which can help us achieve further understanding of immune escape mechanisms in OSCC. We induced human monocytes THP-1 into M0, M1, and M2 macrophages, and applied them to common medium and tumor-conditioned medium, the latter was collected from two types of OSCC cell line. Western blot and RT-PCR were used to detect PD-L1 expression and activation of JAK2/STAT3 pathway in macrophages under various conditions. We found that GM-CSF in tumor-conditioned medium from OSCC cells increased PD-L1 expression in M0 macrophages in a time-dependent manner. Moreover, both GM-CSF neutralizing antibody and JAK2/STAT3 pathway inhibitor AG490 could inhibited its up-regulation. In the meantime, we confirmed that GM-CSF indeed acted through JAK2/STAT3 pathway by measuring phosphorylation of key proteins in this pathway. Therefore, we concluded that OSCC cell-derived GM-CSF was able to up-regulate PD-L1 expression in TAMs through JAK2/STAT3 signaling pathway.

GM-CSF; JAK2/STAT3 signaling pathway; Oral squamous cell carcinoma; PD-L1; tumor-associated macrophages.