Osimertinib Improves the Immune Microenvironment of Lung Cancer by Downregulating PD-L1 Expression of Vascular Endothelial Cells and Enhances the Antitumor Effect of Bevacizumab.

Abstract

Objective To investigate the effect and mechanism of osimertinib combined with bevacizumab on lung cancer through cell and transplanted tumor animal experiments and to provide theoretical basis for further clinical trials. Methods Immunohistochemistry was used to detect the expression of PD-L1 in tumor vessels of nonmetastatic lung adenocarcinoma and metastatic lung adenocarcinoma. At the same time, the expression of CD8 and FoxP3 in tumor tissue was detected. qRT-PCR was used to detect the effect of osimertinib on PD-L1 expression in HUVECs. The expression levels of p-Akt and p-ERK in HUVECs treated with osimertinib were analyzed by Western blot. AKT was blocked by AKT specific inhibitor Ly294002 to analyze the expression of PD-L1 in HUVECs. An animal model of transplanted tumor was constructed to analyze whether osimertinib could enhance the antitumor effect of bevacizumab. Results PD-L1 was highly expressed in vascular endothelial cells of metastatic lung cancer. FoxP3 was highly expressed in metastatic lung adenocarcinoma, while CD8 expression was low. Osimertinib inhibits PD-L1 expression in endothelial cells. Mechanism studies have shown that osimertinib inhibits PD-L1 expression in endothelial cells through the AKT/ERK pathway. Osimertinib inhibited endothelial cell PD-L1 expression, increased CD8+T cell infiltration, inhibited tumor growth, and enhanced the tumor effect of bevacizumab. Conclusion Osimertinib can significantly increase the killing ability of bevacizumab against tumor. Osimertinib can improve the tumor microenvironment and enhance the antitumor effect of bevacizumab by reducing the expression of PD-L1 in tumor blood vessels.