Abstract 576: A novel intestinal microbiome-derived peptide modulates host T cell activation

Abstract

Abstract The microbiome shapes the metabolic and immunological landscape of individuals in health and disease and represents a new robust source of bioactive molecules with therapeutic potential. Second Genome’s large and curated microbiome database coupled with its proprietary bioinformatics and machine learning pipeline enables the discovery of novel microbiome-derived drug candidates across multiple disease areas, including immuno-oncology (IO). Microbial genus Bifidobacterium previously showed a positive association with antitumor T cell responses in mouse models and was overrepresented in melanoma patients responding to immunotherapy with anti-PD-1 antibody. Our hypothesis is that bioactive molecules derived from these Bifidobacteria help drive these antitumor responses and could function as cancer therapeutics or adjuvants for cancer immunotherapy. Thus, we nominated protein and peptide candidates with high scores of secretability, uniqueness, stability, and expressability from Bifidobacterium breve and Bifidobacterium longum genomes for screening in cell-based assays. Initial evaluation of more than 50 Bifidobacterium peptides revealed candidates capable of inducing immune activation. Here, we describe a B. breve-derived peptide (termed SG-B) that induced up-regulation of co-stimulatory (OX40 and ICOS) and inhibitory (PD-1) molecules on CD4+ and CD8+ T cells in both: i) a purified human pan-T cell system; and ii) PBMC cultures stimulated with low-dose anti-CD3 antibody. Furthermore, SG-B stimulated secretion of effector cytokines by in vitro-cultured purified T cells (TNF-a, IL-2, IFN-g, and IL-10) and PBMCs (IL-1b, IL-6, and IL-8). These effects were dose-dependent and evident across multiple human blood donors. In the CT26 syngeneic tumor model, peri-tumoral administration of SG-B induced an increase in the proportion of NK cells and CD4+ T cells within the tumor. The peptide also induced up-regulation of activation marker on CD8+ T cells (CD25, Ki67, and OX40). Collectively, these data suggest that SG-B can modulate adaptive immunity via T cell potentiation and may enhance tumor inflammation in vivo. The peptide’s ability to up-regulate key co-stimulatory and checkpoint molecules on T cells provides a strong rationale for its potential future use in combination with approved or IO agents in current development. These results validate the capability of the Second Genome drug discovery platform to identify novel microbial agents of potential therapeutic relevance in IO and demonstrate a unique approach that can identify microbial factors involved in modulating immune cell effector functions and/or immune cell differentiation. Citation Format: Yuliya V. Katlinskaya, Dhwani Haria, Lily McLaughlin, Sunit Jain, Shoko Iwai, Todd DeSantis, Thomas Weinmaier, Toshi Takeuchi, Anu Hoey, Karim Dabbagh, Kareem Graham, Helena Kiefel. A novel intestinal microbiome-derived peptide modulates host T cell activation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 576.