The AXL-Mediated Modulation of Myeloid-Derived Suppressor Cells (MDSC) in Nasopharyngeal Carcinoma

Abstract AXL has ubiquitous expression in multiple cancers, and is strongly linked to both tumor progression, metastasis, and poor prognosis, as well as anti-tumor immune response suppression and induction of tumor resistance to immunotherapy. Therefore, it is a strong target for cancer intervention. Despite the wide application of AXL inhibitors in clinical trials, the role of AXL in the tumor immune microenvironment (TIME) remains undetermined. Herein, we established cell lines with stable AXL knockdown or overexpression using lentiviral infection. Subsequently, we co-cultured the cells with healthy human blood-derived CD33 + PBMCs. After two days in culture, we assessed the PBMCs differentiation into MDSCs and determined the IL-6 and GM-CSF contents in the co-culture supernatants. Additionally, we subcutaneously administered nasopharyngeal carcinoma (NPC) cells into mice, and evaluated the association between AXL content and MDSC aggregation in the resulting tumors. We demonstrated that AXL is a critical modulator of MDSC differentiation and accumulation in NPC. It modulates IL-6, GM-CSF, and Toll-like receptor contents to achieve the aforementioned actions. Herein, we revealed a strong and direct link between AXL, cytokines in TIME, and MDSC differentiation and accumulation. Our work highlights novel approaches to optimizing existing immunotherapeutic interventions.