Sorafenib inhibits myeloid-derived suppressor cell infiltration in canine transitional cell carcinoma.

Abstract

Myeloid-derived suppressor cells (MDSCs)-immature cells with immunosuppressive properties-are promising therapeutic targets for cancer immunotherapy. However, established therapies targeting MDSCs remain lacking, and novel molecules are needed to regulate MDSCs. Sorafenib, a tyrosine kinase (TRK) inhibitor, suppresses MDSCs. As TRKs regulate chemokine production, we hypothesized that sorafenib inhibits MDSCs by regulating chemokine production. This study aimed to investigate the effect of sorafenib on MDSCs and its underlying mechanism in canine transitional cell carcinoma (cTCC). Sorafenib reduced the number of MDSCs and downregulated CX3CL1 expression in the tumor tissues of cTCC-transplanted mice. Vascular endothelial growth factor A (VEGF-A) and platelet derived growth factor-BB (PDGF-BB) recombinant protein, the target axis of sorafenib, increased CX3CL1 expression in cTCC cell line. Furthermore, a positive correlation was observed between urinary levels of CX3CL1 and VEGF-A in cTCC cases. These results indicated that VEGF-A signaling can regulate CX3CL1 expression. Next, we analyzed whether CX3CL1 accelerates MDSC infiltration. MDSCs expressed CX3CR1, the receptor for CX3CL1, and migrated toward recombinant CX3CL1 protein in a dose-dependent manner. In a cTCC-transplanted mouse model, CX3CL1 depletion or treatment with a CX3CR1 inhibitor showed anti-tumor effects and reduced MDSCs in the tumor tissue. Overall, our results indicated that CX3CL1 promotes MDSC infiltration, and the CX3CL1/CX3CR1 axis could be a therapeutic target for regulating MDSCs in dogs with cTCC.