Effect of fruquintinib on programmed death receptor-1 blockade antitumor immune responses in colorectal cancer.

Abstract

150 Background: Programmed death receptor-1 (PD-1) blockade shows little benefit in the patients with microsatellite-stable colorectal cancer (MSS-CRC).Fruquintinib, a China-made anti-angiogenic drug, applied for third line therapy in mCRC. However, the effects of combination of fruquintinib and PD-1 blockade on MSS-CRC and its relative mechanisms are not well determined. Methods: Syngeneic xenograft mouse models were establish using murine MC38 and CT26 colon cancer cells to assess treatment efficacy. The percentages of immune cells were detected in peripheral blood, spleen and tumor tissues in 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 combination of fruquintinib and sintilimab were verified in the treatment of MSS-CRC patients. Results: Our results showed the combination of fruquintinib and sintilimab exhibited strongest inhibition of tumor growth and achieved 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 CD8+T cells, CD8+TNFα+T cells and CD8+IFNγ+T cells and reduced the ratios of MDSCs and macrophages in mice. No obvious damage was observed in main organs in tumor-bearing mice with the combined treatment. Moreover, the treatment of combination of fruquintinib and sintilimab anti-PD-1 antibodies achieved effective response in five refractory advanced MSS CRC patients. Conclusions: Our results show that combination of fruquintinib and sintilimab synergistically inhibits CRC growth by alterating antitumor immune microenvironment.