Abstract
Abstract The composition of the gut microbiota affects cancer development, progression, and response to therapy. A number of commensal bacteria, including Bifidobacterium, have been associated with increased response to immune checkpoint inhibitors in mouse tumor models and in cancer patients. We hypothesized that secreted peptides or proteins are driving the Bifidobacterium-mediated effects. Using our unique bioinformatic-driven discovery platform we nominated putatively secreted Bifidobacterium-derived peptides for evaluation in immune cell effector assays. We demonstrate that several of the peptides induce secretion of pro-inflammatory cytokines (e.g., IL-6, TNF) by in vitro-generated mouse and human dendritic cells, as well as effector cytokine secretion (e.g., IFNγ, IL-2) by mouse splenic T lymphocytes in vitro. To investigate the function of Bifidobacterium-derived peptides in the context of the tumor microenvironment we injected the candidate peptide SG-A directly into the tumor of CT26 tumor-bearing mice and analyzed the immune phenotype using the Nanostring PanCancer Immune Profiling panel and flow cytometry. Both Nanostring as well as flow cytometry analysis showed an increase in CD45+ tumor-infiltrating lymphocytes in SG-A treated tumors. SG-A peptide also induced the upregulation of dendritic cell function genes (CD40, CD83, and CD86) and multiple effector cytokines and chemokines. Re-stimulation of tumor-draining lymph node cells with AH1 peptide (a CT26 tumor-derived antigen) also increased induction of IFNγ in SG-A treated animals (vs. vehicle-treated controls). Collectively, our results demonstrate the utility of the Second Genome discovery platform for leveraging microbiome science to identify novel immunoregulatory factors. This platform offers a promising approach to identify agents with potential for use as therapeutics in cancer immunotherapy. Citation Format: Helena Kiefel, Dhwani Haria, Yuliya Katlinskaya, Divya Ravichandar, Lily McLaughlin, Sunit Jain, Thomas Weinmaier, Shoko Iwai, Todd DeSantis, Toshi Takeuchi, Karim Dabbagh, Kareem Graham. A novel intestinal microbiome-derived peptide modulates immune cell activity and the tumor microenvironment [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 4963.
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