Eubacterium Rectale Enhances Efficacy Of PD-1-Based Immunotherapy Against Melanoma

Background: Growing evidence supports that gut microbiota influences response to immune therapy through intermediate metabolites or surface antigen structures.Targeting gut microbial community is a promising strategy for enhancing the efficacy of immune checkpoint inhibitor(ICI)against melanoma.Here,we found that Eubacterium rectale(E.rectale)abundance was significantly increased in responders that were treated with ICI from 2 independent and public clinical melanoma cohorts.Therefore,we set out to identify the effect of E.rectale on the response to anti-programmed cell death 1(PD-1)immunotherapy against melanoma.Objective: To explore the antitumor efficacy of E.rectale in combination with PD-1-based immunotherapy against melanoma and to investigate the underlying mechanisms.Methods: We used murine model of melanoma to evaluate whether oral administration of E.rectale improves the efficacy of PD-1-based immunotherapy.We performed flow cytometry analysis in B16F10 tumors to detect the immunological mechanisms of E.rectale-mediated antitumor immunity.An untargeted metabolomics analysis using the gas chromatography-mass spectrometry(GC-MS)system was conducted to identify the differences of metabolic processes between control and the combination of E.rectale and PD-1 m Ab group.In addition,a series of in vitro and in vivo experiments were conducted to explore the molecular mechanisms of E.rectale-mediated antitumor effect.Results: We found that the abundance of E.rectale was significantly increased in responders that were treated with ICI from 2 independent and public clinical melanoma cohorts.We demonstrated that oral administration of live E.rectale augmented the antitumor activity of PD-1-based immunotherapy by increasing tumor-infiltrating NK cells.Moreover,the combination treatment shifted the fecal metabolomics profile towards lower level of L-serine,that were shown to increase tumor-infiltrating NK cells in murine model of B16F10 melanoma.Mechanistically,treatment with live E.rectale or supernatant of E.rectale enhanced the antitumor effects of NK cells by promoting antitumor cytokines and chemokines like PFN2,CCL2,IL-13 and IL-21.Conclusion: Our results suggested that E.rectale mediated antitumor immunity and established an empirical basis for developing oral administration of E.rectale or agents that blocked serine synthesis pathway(SSP)as a combination agent with PD-1 m Ab for melanoma therapies.