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Intestinal barrier dysfunction or the loss of the epithelial integrity allowing the permeation of microorganisms, dietary antigens and other particles into the gastrointestinal (GI) mucosa results in the activation of the immune system and drives inflammation during IBD. Ongoing inflammation in the GI tract and loss of the mucosal barrier are key features of active disease and predict relapse and serious complications. Existing drugs approved in IBD have limited effects on endoscopic remission and improvement in mucosal healing, driving a critical need for therapies which lead directly to mucosal healing. We have identified a microbial protein, SG-2-0776, that directly improves barrier function and reduces fibrogenesis in vitro and in vivo with potential to become a driver of mucosal healing. SG-2-0776 was identified through a novel algorithm, multi-technology meta-analysis (MTMA), using mucosal biopsies from UC patients and control subjects. Two bacterial strains, Eubacterium eligens and Roseburia hominis were significantly reduced in UC samples. Screening of proteins predicted to be secreted from these strains using in vitro transepithelial/endothelial electrical resistance (TEER) and wound healing assays, identified SG-2-0776, a novel protein, which significantly improved epithelial barrier integrity and reduced fibrogenesis. Administration of recombinant SG-2-0776 protein showed improvement in intestinal barrier function, reduced inflammation and fibrosis in rodent models of colitis. Moreover, SG-2-0776 was expressed in Lactococcus lactis as a delivery vehicle and administered orally to act locally for therapeutic effects in these models of colitis. Mechanism of action studies demonstrated that SG-2-0776 interacts with extracellular matrix proteins regulating myofibroblasts differentiation, leading to reduced fibrogenic phenotypes. Altogether, these results demonstrate SG-2-0776 has the potential, as a standalone or adjunct therapy to existing treatments, to ameliorate mucosal barrier function and prevent fibrogenesis in IBD patients.

The gut microbiota has emerged as an important player in cancer pathology, and increasing evidence supports its role in clinical response to immune checkpoint inhibitor (ICI) therapy. However, the specific microbiome-derived factors responsible for the improved response to ICI therapy remain unknown. Second Genome has developed a unique discovery platform to identify, screen, and validate microbiome-derived peptides that promote response to cancer immunotherapy. Using our multitechnology meta-analysis of published datasets and characterizing the baseline microbiome of melanoma patients treated with anti-PD-1, we have identified gut microbiome strains differentially abundant in responders versus nonresponders that are concordant across multiple cohorts. Next, peptides from strains associated with responder signatures were predicted from their genome sequences. In addition, we predicted peptides from assembled metagenomes that were associated with responders. The predicted peptides were screened using phage display technology to identify binders to immune cells known to play a role in the tumor microenvironment (TME). Peptides that bound to specific immune cells were then evaluated for activity in cell-based assays using isolated primary human T cells, dendritic cells (DCs), and macrophages. We have demonstrated that several microbiome-derived peptides induce secretion of proinflammatory cytokines and chemokines such as CXCL10 and TNF-α by primary human monocyte-derived dendritic cells (moDCs), as well as secretion of effector cytokines such as IFNγ and IL-2 by primary human T cells. We have also identified microbiome-derived peptides with the capacity to inhibit an M2-like phenotype in macrophages (decreased LPS-induced IL-10 secretion). These effects were dose dependent and evident across immune cells derived from multiple human blood donors. In a coculture assay using allogeneic moDCs and T cells from human donors, combination of our DC-activating peptides with CD40 agonistic antibody and/or anti-PD-L1 induced secretion of proinflammatory cytokines such as IFNγ and TNF-α. In vivo, peritumoral administration of a candidate DC-activating peptide into RENCA tumor-bearing mice led to a significant reduction in tumor volume as compared to the control-treated mice. Collectively, these data demonstrate the potential of the microbiome-derived peptides identified by Second Genome’s discovery platform to modulate immune-cell effector functions in vitro and promote antitumor immunity in vivo. These results validate the unique approach of Second Genome’s discovery platform to identify novel microbiome-derived agents with potential for use as therapeutics in cancer immunotherapy. This abstract is also being presented as Poster B19. Citation Format: Dhwani D. Haria, Jayamary Divya Ravichandar, Lynn Yamamoto, Bernat Baeza-Raja, Ashil Bans, Cheryl-Emiliane Chow, Jill Desnoyer, Joanna Dreux, Shoko Iwai, Sabina Lau, Jina Lee, Michelle Lin, Paul Loriaux, Nicole Narayan, Eskedar Nigatu, Erica Rutherford, Michi Wilcoxon, Yonggan Wu, Todd DeSantis, Toshihiko Takeuchi, Karim Dabbagh, Helena Kiefel. Novel microbiome-derived peptides modulate immune cell activity and the tumor microenvironment [abstract]. In: Proceedings of the AACR Special Conference on the Microbiome, Viruses, and Cancer; 2020 Feb 21-24; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2020;80(8 Suppl):Abstract nr PR08.