摘要
Although interferonα(IFNα)and anti-angiogenesis antibodies have shown appropriate clinical benefit in the treatment of malignant cancer,they are deficient in clinical applications.Previously,we described an anti-vascular endothelial growth factor receptor 2(VEGFR2)-IFNαfusion protein named JZA01,which showed increased in vivo half-life and reduced side effects compared with IFNα,and it was more effective than the anti-VEGFR2 antibody against tumors.However,the affinity of the IFNv component of the fusion protein for its receptor-IFNAR1 was decreased.To address this problem,an IFNα-mutant fused with anti-VEGFR2 was designed to produce anti-VEGFR2-IFNamut,which was used to target VEGFR2 with enhanced anti-tumor and anti-metastasis efficacy.Anti-VEGFR2-IFNamut specifically inhibited proliferation of tumor cells and promoted apoptosis.In addition,antiVEGFR2-IFNαmut inhibited migration of colorectal cancer cells and invasion by regulating the PI3 K-AKT-GSK3β-snail signal pathway.Anti-VEGFR-2-IFNamut showed superior anti-tumor efficacy with improved tumor microenvironment(TME)by enhancing dendritic cell maturation,dendritic cell activity,and increasing tumor-infiltrating CD8+T cells.Thus,this study provides a novel approach for the treatment of metastatic colorectal cancer,and this design may become a new approach to cancer immunotherapy.
基金
supported by grants from“Double First-Class”University Project(CPU2018PZQ12 and CPU2018GY14,China)
National Natural Science Foundation of China(Grant 81993223)
National Natural Science Foundation of China(Grant 81773755)
Natural Science Foundation of Jiangsu Province(BK20161459,China)
Postgraduate Research&Practice Innovation Program of Jiangsu Province(SJCX19_0162,China)
the National Students’Platform for Innovation and Entrepreneurship Training Program(201810316010Y,China)