biostudies-literatureUnknown16Bardouillet L<h4>Background</h4>Advancing research in oncology highlights the inverse correlation between antibiotic treatment and the positive outcomes of immune checkpoint inhibitor (ICI) administration, confirming once more the importance of microbiota and microbiota-derived compounds as complementary tools for treating cancer. Among the immune checkpoints, the CD200 cell surface glycoprotein has gained attention for its role in promoting self-tolerance and potentially facilitating tumor growth through interaction with the CD200R1 receptor.<h4>Methods</h4>We developed a robust AlphaLISA-based screening to identify human gut microbiota-derived proteins that may interact with CD200R1 and screened a library of 10,966 gut bacterial proteins. The antitumor activity of BOC1 was investigated <i>in vitro</i> by cytokine analysis, mixed lymphocyte reactions, and myeloid-derived suppressor cell (MDSC)-T-cell suppression assay. AlphaFold modeling was used to predict potential interaction points between BOC1 and CD200R1.<h4>Results</h4>We successfully identified BOC1, a protein from the <i>Bacteroides</i> genus, showing better affinity than the natural ligand, CD200, toward the CD200R1 receptor. BOC1 induces cytokine secretion by monocyte-derived dendritic cells (MoDCs) and enhances CD8⁺/CD4⁺ T-cell populations and IFNγ production, highlighting its potent immunostimulatory properties. BOC1 also negatively impacts the differentiation of MDSCs, maintaining an immature monocytic profile (high CD14 and HLA-DR expression) and restoring T-cell proliferation even at low (10 nM) concentration. Mutation of amino acids within the N-terminal region of BOC1 reduces binding to CD200R1, supporting the importance of this region for a possible interaction with CD200R1.<h4>Conclusion</h4>The immunostimulatory properties of BOC1 observed <i>in vitro</i> are compatible with an ICI-like behavior of this bacterial protein. Given that neither the CD200 protein nor the anti-CD200 antibody is able to compete with BOC1 for binding to CD200R1, and as supported by AlphaFold modeling predictions, CD200 and BOC1 might target different regions of CD200R1.Frontiers in immunology1607543https://www.ebi.ac.uk/biostudies/studies/S-EPMC12401969biostudies-literatureThe gut microbiota protein BOC1 exhibits immune checkpoint inhibitor-like activity by inhibiting myeloid-derived suppressor cell differentiation.PMC12401969Bardouillet LCultrone AThomas VStrozzi FMatondo COrsini Delgado MLChene LfalseThe gut microbiota protein BOC1 exhibits immune checkpoint inhibitor-like activity by inhibiting myeloid-derived suppressor cell differentiation.<h4>Background</h4>Advancing research in oncology highlights the inverse correlation between antibiotic treatment and the positive outcomes of immune checkpoint inhibitor (ICI) administration, confirming once more the importance of microbiota and microbiota-derived compounds as complementary tools for treating cancer. Among the immune checkpoints, the CD200 cell surface glycoprotein has gained attention for its role in promoting self-tolerance and potentially facilitating tumor growth through interaction with the CD200R1 receptor.<h4>Methods</h4>We developed a robust AlphaLISA-based screening to identify human gut microbiota-derived proteins that may interact with CD200R1 and screened a library of 10,966 gut bacterial proteins. The antitumor activity of BOC1 was investigated <i>in vitro</i> by cytokine analysis, mixed lymphocyte reactions, and myeloid-derived suppressor cell (MDSC)-T-cell suppression assay. AlphaFold modeling was used to predict potential interaction points between BOC1 and CD200R1.<h4>Results</h4>We successfully identified BOC1, a protein from the <i>Bacteroides</i> genus, showing better affinity than the natural ligand, CD200, toward the CD200R1 receptor. BOC1 induces cytokine secretion by monocyte-derived dendritic cells (MoDCs) and enhances CD8⁺/CD4⁺ T-cell populations and IFNγ production, highlighting its potent immunostimulatory properties. BOC1 also negatively impacts the differentiation of MDSCs, maintaining an immature monocytic profile (high CD14 and HLA-DR expression) and restoring T-cell proliferation even at low (10 nM) concentration. Mutation of amino acids within the N-terminal region of BOC1 reduces binding to CD200R1, supporting the importance of this region for a possible interaction with CD200R1.<h4>Conclusion</h4>The immunostimulatory properties of BOC1 observed <i>in vitro</i> are compatible with an ICI-like behavior of this bacterial protein. Given that neither the CD200 protein nor the anti-CD200 antibody is able to compete with BOC1 for binding to CD200R1, and as supported by AlphaFold modeling predictions, CD200 and BOC1 might target different regions of CD200R1.2025-01-01T00:00:00Z20252026-05-29T21:36:52.64Z2026-04-08T06:05:01.32ZS-EPMC124019694090446610.3389/fimmu.2025.1607543