@article {Tang401, author = {Honglin Tang and Yanzhuo Liu and Chenlong Wang and Hao Zheng and Yaxin Chen and Wen Liu and Xuewei Chen and Jing Zhang and Honglei Chen and Yuqing Yang and Jing Yang}, title = {Inhibition of COX-2 and EGFR by Melafolone Improves Anti-PD-1 Therapy through Vascular Normalization and PD-L1 Downregulation in Lung Cancer}, volume = {368}, number = {3}, pages = {401--413}, year = {2019}, doi = {10.1124/jpet.118.254359}, publisher = {American Society for Pharmacology and Experimental Therapeutics}, abstract = {Checkpoint blockade therapy has been proven efficacious in lung cancer patients. However, primary/acquired resistance hampers its efficacy. Therefore, there is an urgent need to develop novel strategies to improve checkpoint blockade therapy. Here we tested whether dual inhibition of cyclooxygenase-2 (COX-2) and epidermal growth factor receptor (EGFR) by flavonoid melafolone improves program death 1 (PD-1) checkpoint blockade therapy through normalizing tumor vasculature and PD-1 ligand (PD-L1) downregulation. Virtual screening assay, cellular thermal shift assay, and enzyme inhibition assay identified melafolone as a potential inhibitor of COX-2 and EGFR. In Lewis lung carcinoma (LLC) and CMT167 models, dual inhibition of COX-2 and EGFR by melafolone promoted survival, tumor growth inhibition, and vascular normalization, and ameliorated CD8+ T-cell suppression, accompanied by the downregulation of transforming growth factor-β (TGF-β), vascular endothelial growth factor (VEGF), and PD-L1 in the tumor cells. Mechanistically, dual inhibition of COX-2 and EGFR in lung cancer cells by melafolone increased the migration of pericyte, decreased the proliferation and migration of endothelial cells, and enhanced the proliferation and effector function of CD8+ T cells through VEGF, TGF-β, or PD-L1 downregulation and PI3K/AKT inactivation. Notably, melafolone improved PD-1 immunotherapy against LLC and CMT167 tumors. Together, dual inhibition of COX-2 and EGFR by melafolone improves checkpoint blockade therapy through vascular normalization and PD-L1 downregulation and, by affecting vessels and immune cells, may be a promising combination strategy for the treatment of human lung cancer.}, issn = {0022-3565}, URL = {https://jpet.aspetjournals.org/content/368/3/401}, eprint = {https://jpet.aspetjournals.org/content/368/3/401.full.pdf}, journal = {Journal of Pharmacology and Experimental Therapeutics} }