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

Intestinal microbiota and gut-born T helper-17 (Th17) lymphocytes may act as drivers of smoldering multiple myeloma (SMM) to MM evolution. We demonstrate here that administering the human commensal Prevotella melaninogenica to transgenic Vk*MYC mice affected by Early-MM, mimicking human SMM, significantly delayed evolution to full-blown MM. Mechanistically, P. melaninogenica increased the production of short-chain fatty acids (SCFAs), preventing skew of dendritic cells towards a pro-Th17 phenotype and accumulation of Th17 cells in the bone marrow of treated mice. P. melaninogenica or butyrate synergized with anti-PD-L1 antibodies by restraining Th17 cell expansion while unleashing immune checkpoint blockade (ICB)-induced effector CD8+ T cells. P. melaninogenica also attenuated IL-17-mediated skin lesions that mimicked ICB-induced immune-related adverse events. Thus, modulation of the gut microbiota or SCFAs administration with or without ICB might represent treatment options for patients affected by plasma cell dyscrasias and other hematologic or solid tumors where IL-17 acts as driving force.