Department of Oncology, The First Affiliated Hospital with Nanjing Medical University, Nanjing 210029, China.
Department of Oncology, Cancer Rehabilitation Center, Jiangsu Province Hospital, Nanjing 210029, China.
J Immunol. 2020 Nov 15;205(10):2905-2915. doi: 10.4049/jimmunol.2000463. Epub 2020 Oct 7.
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.
鉴定结直肠癌（CRC）的有效疗法仍然是一个迫切的医学需求，尤其是对于微卫星稳定（MSS）表型。在本研究中，研究了联合使用呋喹替尼加抗 PD-1 治疗 MSS CRC。首先报告了一例晚期 MSS CRC 病例。在多线治疗失败后，患者最终在接受呋喹替尼加抗 PD-1 治疗后迅速缓解。然后使用 CT26 细胞（MSS）的小鼠同源同种型模型验证了呋喹替尼加抗 PD-1 的疗效。结果表明，与单独使用单一药物相比，联合治疗可显著抑制肿瘤生长并延长荷瘤小鼠的生存时间。此外，呋喹替尼/抗 PD-1 联合治疗可减少血管生成，增强血管结构的正常化，并减轻肿瘤缺氧。此外，联合治疗通过增强趋化因子释放、增加 CD8 T 细胞浸润和激活、减少调节性 T 细胞比例以及促进巨噬细胞 M1/M2 比值来重新编程免疫微环境。最后，与野生型小鼠相比，CD8 基因敲除小鼠中呋喹替尼/抗 PD-1 联合治疗的抗肿瘤增强作用明显逆转。我们的研究表明，呋喹替尼和抗 PD-1 的联合使用可以协同抑制 CRC 进展，并改变有利于抗肿瘤免疫反应的肿瘤微环境。
