Host-microbe interactions mediating antitumorigenic effects of MRX0518, a gut microbiota-derived bacterial strain, in breast, renal and lung carcinoma.

e15006 Background: The gut microbiota is a key player in therapeutic response to cancer treatment and is linked to the efficacy of checkpoint inhibitors. Proposed antitumorigenic mechanisms of commensal bacteria include expansion of (tumor-specific) T cells, activation of dendritic cells and modulation of the gut microbiota. We examined the antitumor effects of the commensal isolate MRx0518, Enterococcus gallinarum, and analyzed its active compounds and immunotherapy targets. Methods: MRx0518 efficacy on tumor growth was assessed in syngeneic mouse models of breast, renal and lung carcinoma. Tumor flow cytometry, cytokine profiling, transcriptomics, immunohistochemistry and microbiota analysis was performed. MRx0518-induced cytokine production and activation of immunotherapy-relevant cell types was investigated in vitro. Intra-species comparative genomics of MRx0518 was performed, and the transcriptional and proteomic signature associated with host cell activation was assessed. A mono-colonized mouse model was used to study host-microbe interactions in vivo. Results: MRx0518 monotherapy reduced tumor size between 35-51% compared to controls. Tumor reduction corresponded to an increased CD8+ T cells:Tregs ratio and decreased Ki67+ cells. 16S gut microbiota profiling showed a significantly increased diversity for Observed Species. MRx0518 antitumor activity was linked to a strong in vitro immuno-stimulatory phenotype characterized by a distinct transcriptomic signature and induction of inflammatory mediators (IL-8, TNF-α, IL-1ß, IL-6, IL-23, CXCL9, CXCL10). The relative proliferation and activation of CD4+, CD8+ and regulatory T cells was also measured. The MRx0518 genome contained strain-specific regions, and putative immunomodulatory effectors were identified. Mono-colonization studies in germfree mice showed interactions between MRx0518 and activated gut immune cell populations. Conclusions: The gut microbiota-derived strain MRx0518 displays strong antitumor efficacy, and active microbial signaling compounds have been identified. Clinical studies in a variety of solid tumors are planned to commence shortly.