Pools of programmed death-ligand within the oral cavity tumor microenvironment: Variable alteration by targeted therapies

Background: Enhanced understanding of programmed death-ligand (PD-L) expression in oral cancer is important for establishing rational combinations of emerging immune checkpoint and molecular targeted therapies. Methods: We assessed PD-L and interferon (IFN) expression in immunogenic murine oral cancer-1 (MOC1) and poorly immunogenic MOC2 cell models after treatment with mammalian target of rapamycin (mTOR) and MEK1/2 small molecule inhibitors in vitro and in vivo. Results: PD-L1 but not PD-L2 is expressed on MOC1 and 2 cells and is type I and II IFN-dependent. PD-L1 is differentially expressed on cancer and endothelial cells and infiltrating myeloid-derived suppressor cells, macrophages, and regulatory T cells (Tregs) in highly and poorly immunogenic tumors. PD-L1 expression is variably altered after treatment with inhibitors in vivo, with an imperfect relationship to alterations in IFN levels in the tumor microenvironment. Conclusion: PD-L1 expressed on cancer and infiltrating immune cells is variably altered by targeted therapies and may, in part, reflect changes in tumor IFN.