Inhibition of COX-2 and EGFR by Melafolone Improves Anti-PD-1 Therapy through Vascular Normalization and PD-L1 Downregulation in Lung Cancer
Inhibition of COX-2 and EGFR by Melafolone Improves Anti-PD-1 Therapy through Vascular Normalization and PD-L1 Downregulation in Lung Cancer
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Melafolone 抑制 COX-2 和 EGFR 通过血管正常化和肺癌 PD-L1 下调改善抗 PD-1 治疗
DOI：
10.1124/jpet.118.254359
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发表时间：
2019-03-01
影响因子：
3.5
通讯作者：
Yang, Jing
中科院分区：
文献类型：
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作者：
Tang, Honglin;Liu, Yanzhuo;Yang, Jing
检查点阻断疗法已被证明在肺癌患者中有效。然而，原发性/获得性抗性阻碍了其功效。因此，迫切需要开发新的策略来改善检查点阻断疗法。在这里，我们测试了类黄酮美拉福龙对环氧合酶-2（考克斯-2）和表皮生长因子受体（EGFR）的双重抑制是否通过使肿瘤血管系统和PD-1配体（PD-L1）下调正常化来改善程序性死亡1（PD-1）检查点阻断疗法。虚拟筛选试验、细胞热位移试验和酶抑制试验证实美拉福龙是考克斯-2和EGFR的潜在抑制剂。在刘易斯肺癌（LLC）和CMT 167模型中，美拉福龙对考克斯-2和EGFR的双重抑制促进了生存、肿瘤生长抑制和血管正常化，并改善了CD 8 + T细胞抑制，伴随着肿瘤细胞中转化生长因子-β（TGF-β）、血管内皮生长因子（VEGF）和PD-L1的下调。机制上，美拉福龙对肺癌细胞中考克斯-2和EGFR的双重抑制增加了周细胞的迁移，降低了内皮细胞的增殖和迁移，并通过VEGF、TGF-β或PD-L1下调和PI 3 K/AKT失活来增强CD 8 + T细胞的增殖和效应功能。值得注意的是，melafolone改善了针对LLC和CMT 167肿瘤的PD-1免疫疗法。总之，美拉福龙对考克斯-2和EGFR的双重抑制通过血管正常化和PD-L 1下调来改善检查点阻断治疗，并且通过影响血管和免疫细胞，可能是治疗人类肺癌的一种有希望的联合策略。
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.