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

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.

A novel immune checkpoint siglec-15 antibody inhibits LUAD by modulating mφ polarization in TME.

BACKGROUND: Siglec-15 (S15) is a type-I transmembrane protein and is considered a new candidate of immune checkpoint inhibitor for cancer immunotherapy. METHODS: In the present study, we first constructed and characterized a chimeric S15-specific monoclonal antibody (S15-4E6A). Then, the antitumor effectiveness and modulatory role of S15-4E6A in macrophages (mφs) were explored in vitro and in vivo. Finally, the underlying mechanism by which S15mAb inhibits LUAD was preliminarily explored. RESULTS: The results demonstrated the successful construction of S15-4E6A, and S15-4E6A exerted an efficacious tumor-inhibitory effect on LUAD cells and xenografts. S15-4E6A could promote M1-mφ polarization while inhibiting M2-mφ polarization, both in vitro and in vivo. CONCLUSIONS: S15-based immunotherapy that functions by modulating mφ polarization may be a promising strategy for the treatment of S15-positive LUAD.