Combination of Fruquintinib and Anti–PD-1 for the Treatment of Colorectal Cancer
Yuanyuan Wang, Bin Wei, Jianhua Gao, Xiaomin Cai, Lingyan Xu, Haiqing Zhong, Binglin Wang, Yang Sun, Wenjie Guo, Qiang Xu, Yanhong Gu
Abstract
Abstract Identification of effective therapies for colorectal cancer (CRC) remains an urgent medical need, especially for the microsatellite-stable (MSS) phenotype. In the current study, a combination of fruquintinib plus anti–PD-1 for MSS CRC therapy was investigated. First, a case of advanced MSS CRC was reported. After failure of multiline therapy, the patient finally achieved rapid response after receiving fruquintinib plus anti–PD-1 treatment. Then the effect of fruquintinib plus anti–PD-1 was verified using a murine syngeneic model of CT26 cells (MSS). The results showed that cotreatment significantly inhibited tumor growth and promote survival time for tumor-bearing mice compared with the single drug alone. In addition, fruquintinib/anti–PD-1 cotreatment decreased angiogenesis, enhanced normalization of the vascular structure, and alleviated tumor hypoxia. Moreover, the combination therapy reprogrammed the immune microenvironment by enhancing chemotactic factor release, increasing CD8+ T cell infiltration and activation, decreasing ration of regulatory T cells, and promoting M1/M2 ratio of macrophage. Finally, the enhanced antitumor effect of fruquintinib/anti–PD-1 cotreatment was significantly reversed in CD8 knockout mice compared with that in the wild-type mice. Our study indicated that combination of fruquintinib and anti–PD-1 could synergistically suppress CRC progression and altered the tumor microenvironment in favor of antitumor immune responses.