Li Qingli, Cheng Xiaojiao, Zhou Cong, Tang Yao, Li Fuli, Zhang Baiwen, Huang Tinglei, Wang Jianzheng, Tu Shuiping
State Key Laboratory of Oncogenesis and Related Genes, Department of Oncology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
Department of Oncology, Henan Cancer Hospital, The Affiliated Cancer Hospital of Zhengzhou University, Zhengzhou, China.
Front Oncol. 2022 Mar 17;12:841977. doi: 10.3389/fonc.2022.841977. eCollection 2022.
Programmed death receptor-1 (PD-1) blockade shows little benefit in patients with microsatellite-stable colorectal cancer (MSS-CRC). Fruquintinib is a China-made anti-angiogenic drug which is approved for the third line therapy in mCRC. This study investigates the effect of the combination of fruquintinib and PD-1 blockade on MSS-CRC and its relative mechanisms.
The mouse allograft tumor models that represent MSS and microsatellite instability (MSI) CRC were established using murine CT26 and MC38 colon cancer cells, respectively, to assess the treatment efficacy. The percentages of immune cells were detected in the peripheral blood, spleen and tumor tissues in the tumor-bearing mice by flow cytometry analysis. Angiogenesis in tumor tissues was detected by immunofluorescence. The safety of drug treatment was evaluated by histopathology analysis in murine main organs. The efficacy of the combination of fruquintinib and sintilimab were verified in the treatment of MSS-CRC patients.
Our results showed that the combination of fruquintinib and sintilimab exhibited the strongest inhibition of tumor growth and achieved the longest survival time in mice bearing MC38 or CT26 xenograft tumors, compared to fruquintinib and sintilimab alone. Mechanistically, the combination of fruquintinib and sintilimab reduced angiogenesis, reprogramed the vascular structure, enhanced the infiltration of CD8T cells (p<0.05), CD8TNFα (p<0.05) T cells and CD8IFNγ (p<0.05) T cells and reduced the ratios of MDSCs and macrophages in mice. There was no obvious toxicity observed in the main organs of the tumor-bearing mice with the combined treatment. Moreover, the treatment using the combination of fruquintinib and sintilimab achieved effective response in five patients with refractory advanced MSS CRC.
Our results show that the combination of fruquintinib and sintilimab greatly inhibits CRC growth by altering tumor immune microenvironment. This study provides the rational for using the combination of fruquintinib and anti-PD-1 antibody for the treatment of advanced CRC.
程序性死亡受体-1（PD-1）阻断疗法对微卫星稳定型结直肠癌（MSS-CRC）患者益处不大。呋喹替尼是一种国产抗血管生成药物，被批准用于转移性结直肠癌（mCRC）的三线治疗。本研究探讨呋喹替尼与PD-1阻断联合应用对MSS-CRC的疗效及其相关机制。
分别使用小鼠CT26和MC38结肠癌细胞建立代表MSS和微卫星不稳定（MSI）结直肠癌的小鼠异种移植瘤模型，以评估治疗效果。通过流式细胞术分析检测荷瘤小鼠外周血、脾脏和肿瘤组织中免疫细胞的百分比。通过免疫荧光检测肿瘤组织中的血管生成。通过对小鼠主要器官进行组织病理学分析评估药物治疗的安全性。在MSS-CRC患者的治疗中验证了呋喹替尼与信迪利单抗联合应用的疗效。
我们的结果表明，与单独使用呋喹替尼和信迪利单抗相比，呋喹替尼与信迪利单抗联合应用对携带MC38或CT26异种移植瘤的小鼠具有最强的肿瘤生长抑制作用，并实现了最长的生存时间。从机制上讲，呋喹替尼与信迪利单抗联合应用可减少血管生成，重塑血管结构，增强CD8T细胞（p<0.05）、CD8TNFα（p<0.05）T细胞和CD8IFNγ（p<0.05）T细胞的浸润，并降低小鼠骨髓来源抑制细胞（MDSCs）和巨噬细胞的比例。联合治疗的荷瘤小鼠主要器官未观察到明显毒性。此外，呋喹替尼与信迪利单抗联合治疗在5例难治性晚期MSS CRC患者中取得了有效反应。
我们的结果表明，呋喹替尼与信迪利单抗联合应用通过改变肿瘤免疫微环境极大地抑制了CRC的生长。本研究为使用呋喹替尼与抗PD-1抗体联合治疗晚期CRC提供了理论依据。
