Department of Microbiological & Biochemical Pharmacy, School of Pharmacy, Fudan University, 201203, Shanghai, China.
Minhang Branch, Zhongshan Hospital, Fudan University, 201199, Shanghai, China.
Cell Death Dis. 2018 Oct 10;9(10):1039. doi: 10.1038/s41419-018-1099-3.
Diosgenin, a natural steroidal saponin, can exert antitumor effect by regulating immune function and improving intestinal microbiota. The response to anti-PD-1 immunotherapy is associated with intestinal microbiota and effector T cells in tumor microenvironment. We hypothesize that the modulation of diosgenin on intestinal microbiota can facilitate antitumor immunity and the therapeutic efficacy of PD-1 antibody. In melanoma-bearing C57BL/6 mice, we observed that the anti-melanoma effect of diosgenin relied more on antitumor immunity than direct tumor inhibition activity evidenced by obvious CD4/CD8 T-cell infiltration and IFN-γ expression in tumor tissues, and it could improve the compositions of intestinal microbiota. Antibiotics impaired the therapeutic efficacy and immunity responses of diosgenin through disturbing intestinal microbiota, indicating the importance of intestinal microbiota in diosgenin's in vivo antitumor activity. More importantly, the combined administration of PD-1 antibody with diosgenin aggravated the tumor necrosis and apoptosis by eliciting augmented T-cell responses. Taken together, diosgenin can be used as a microecological regulator to induce antitumor immunity and improve the efficacy of immune checkpoint antibody, making it more suitable for the treatment of malignant tumors.
薯蓣皂苷元是一种天然甾体皂苷，可通过调节免疫功能和改善肠道微生物群来发挥抗肿瘤作用。对 PD-1 免疫疗法的反应与肿瘤微环境中的肠道微生物群和效应 T 细胞有关。我们假设薯蓣皂苷元对肠道微生物群的调节可以促进抗肿瘤免疫和 PD-1 抗体的治疗效果。在荷黑素瘤的 C57BL/6 小鼠中，我们观察到薯蓣皂苷元的抗黑素瘤作用更多地依赖于抗肿瘤免疫，而不是直接的肿瘤抑制活性，这表现在肿瘤组织中明显的 CD4/CD8 T 细胞浸润和 IFN-γ表达，并且可以改善肠道微生物群的组成。抗生素通过扰乱肠道微生物群来损害薯蓣皂苷元的治疗效果和免疫反应，表明肠道微生物群在薯蓣皂苷元体内抗肿瘤活性中的重要性。更重要的是，PD-1 抗体与薯蓣皂苷元联合给药通过引发增强的 T 细胞反应加剧了肿瘤坏死和凋亡。总之，薯蓣皂苷元可用作微生物调节剂来诱导抗肿瘤免疫并提高免疫检查点抗体的疗效，使其更适合恶性肿瘤的治疗。
