Rhamnazin Enhanced Anti-Tumor Efficacy of Anti-PD-1 Therapy for Lung Cancer in Mice through Inhibition of PD-L1 Expression

Rhamnazin Enhanced Anti-Tumor Efficacy of Anti-PD-1 Therapy for Lung Cancer in Mice through Inhibition of PD-L1 Expression

Shu Shi Wang,¹ Ye Liu,² Xuan Ting Zhang³ and Dong Qiang Yu⁴

¹Department of Oncology, Zouping People's Hospital, Zouping, Shandong, China
²Health Institute of Shandong Labor Vocational and Technical College, Jinan, Shandong, China
³Department of Respiratory and Critical Care Medicine, Qingdao Central Hospital Affiliated to Qingdao University, Qingdao, Shandong, China
⁴Department of Emergency Internal Medicine, Affiliated Hospital of Qingdao University, Qingdao, Shandong, China

Emerging studies suggest the significance of broadening the benefit of anti-programmed cell death 1 (PD-1) therapy for lung cancer. The anti-angiogenic agents have been reported to alter the tumor microenvironment and contributes to efficiency of anti-PD-1 therapy. This study aims to investigate whether the anti-angiogenic agent rhamnazin enhances the efficacy of anti-PD-1 therapy in lung cancer. In Lewis lung carcinoma (LLC) xenografts, the combination of rhamnazin and anti-PD-1 treatment suppressed tumor growth, elevated the infiltration of CD4⁺ T and CD8⁺ T cells in tumors and up-regulated interferon-gamma (IFN-γ), tumor necrosis factor alpha (TNF-α), and granzyme B. Furthermore, the combination reduced programmed cell death ligand 1 (PD-L1) expression in tumors more significant than anti-PD-1 treated group. In LLC cell experiments, rhamnazin inhibited vascular endothelial growth factor A (VEGFA)-stimulated vascular endothelial growth factor receptor 2 (VEGFR2) phosphorylation and PD-L1 expression, whereas VEGFR2 overexpression reversed these trends. T cell proliferation and cytotoxic factor production were evaluated after co-culturing with non-small cell lung cancer (NSCLC) H1975 cells. Rhamnazin promotes T cell proliferation and up-regulated IFN-γ, TNF-α and granzyme B in the co-culture system, while VEGFR2 overexpression abrogated these changes. These data suggest that rhamnazin enhances anti-tumor effect of anti-PD-1 therapy for lung cancer in mice via inhibition of PD-L1 expression.

Key words —— anti-PD-1 therapy; lung cancer; PD-L1; VEGFR2

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Tohoku J. Exp. Med 2023 May, 260(1), 63-73.

Correspondence: Dong Qiang Yu, Department of Emergency Internal Medicine, Affiliated Hospital of Qingdao University, 1677 Wutaishan Road, Huangdao Development District, Qingdao, Shandong 266555, China.

e-mail: mercuryhm@tom.com