Microbiome Modulation Uncouples Efficacy and Toxicity Induced by Programmed Death-1/Programmed Death-Ligand1 Blockade

While asymptomatic smoldering multiple myeloma (SMM) holds an overall risk of progression to multiple myeloma (MM) at 10% per year, only active surveillance is offered to most patients affected by SMM, which leaves them in anxiety and frustration. Intestinal microbiota and gut-born T helper 17 (Th17) lymphocytes may act as drivers of MM evolution. In transgenic Vk*MYC mice developing de novo MM, which invariably evolves from Early-MM that mimics SMM to full-blown Late-MM, we investigated the impact of gut microbiota modulation on disease progression and susceptibility to immune checkpoint blockade (ICB). We report that administering the human commensal Prevotella melaninogenica to mice affected by Early-MM significantly delayed evolution to Late-MM. Mechanistically, treatment with P. melaninogenica induced increased production of short chain fatty acids. Butyrate prevented skew of dendritic cells towards a pro-Th17 phenotype and treated mice accumulated less disease induced Th17 cells in their bone marrow. P. melaninogenica also synergized with anti-PD-L1 antibodies by restraining Th17 cell expansion while unleashing ICB-induced full effector CD8+ T cells, eventually blocking progression to full-blown disease. Similar results were obtained in mice challenged with bortezomib-resistant Vk*MYC tumor cells, a model of more aggressive MM. When mice were exposed to imiquimod to mimic ICB-associated psoriasis-like lesions, P. melaninogenica ameliorated skin lesions caused by ICB. Thus, modulation of the gut microbiota with P. melaninogenica might represent a treatment for patients affected by SMM and would allow fully exploiting the antitumor potential of ICB in plasma cell dyscrasias. Key points ### Competing Interest Statement M.B. is co-owner of the patent EP18209623.0, Strategies to improve colonization and expression of Prevotella melaninogenica in the gut of patients affected by IL-17-mediated diseases