Abstract
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.
Highlights
Tumor immunotherapy has aroused general concern due to its capacity to enhance the host’s immune surveillance to recognize tumor cells, and make use of autoimmune function to eradicate tumor and produce sustained antitumor immune response[1]
There are two studies that highlight the key role of the intestinal microbiota in mediating tumor response to immune checkpoint inhibitors: (1) The antitumor efficacy of CTLA-4 antibody depended on the immunostimulatory effect of intestinal microbiota, in which distinct bacterial species could promote the maturation of intratumoral dendritic cells and induced interleukin-12-dependent Th1 immune response[14]
Taking into consideration that the efficacy of PD-1 antibody was influenced by intestinal microbiota and positively correlated with the number of effector T cells in the tumor microenvironment[26,27], this study further explores whether the diosgenin-induced intestinal microbiota modulation and antitumor immunity can improve the therapeutic efficacy of PD-1 antibody
Summary
Tumor immunotherapy has aroused general concern due to its capacity to enhance the host’s immune surveillance to recognize tumor cells, and make use of autoimmune function to eradicate tumor and produce sustained antitumor immune response[1]. Numerous researches suggest that regulating the microbiota may modulate cancer immunotherapy and promote the efficacy of immune checkpoint antibodies[11,12,13]. There are two studies that highlight the key role of the intestinal microbiota in mediating tumor response to immune checkpoint inhibitors: (1) The antitumor efficacy of CTLA-4 antibody depended on the immunostimulatory effect of intestinal microbiota, in which distinct bacterial species could promote the maturation of intratumoral dendritic cells and induced interleukin-12-dependent Th1 immune response. Prior or concomitant modulation of the intestinal microbiota can optimize treatment outcomes of immune checkpoint inhibitors[8]. This phenomenon has been further confirmed in human cancer patients. Three recent published studies reported that intestinal commensal microbiome was closely related to the efficacy of anti-PD-1 immunotherapy in melanoma and epithelial cancer patients[15,16,17]
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