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Microbiome modulation uncouples efficacy and toxicity induced by immune checkpoint blockade in mouse multiple myeloma
Laura Lucia Cogrossi (Vita-Salute San Raffaele University, IRCCS Ospedale San Raffaele), Anna Policastro (IRCCS Ospedale San Raffaele), Paola Zordan (IRCCS Ospedale San Raffaele), Matteo Grioni (IRCCS Ospedale San Raffaele), Anna Tosi (Istituto Oncologico Veneto), Nathalie RIZZO (IRCCS Ospedale San Raffaele), Benedetta Mattorre (IRCCS Ospedale San Raffaele), Marco Lorenzoni (IRCCS Ospedale San Raffaele), Greta Meregalli (IRCCS Ospedale San Raffaele), Sofia Sisti (Vita-Salute San Raffaele University, IRCCS Ospedale San Raffaele), Francesca Sanvito (IRCCS Ospedale San Raffaele), Alessandro Palmioli (University of Milano-Bicocca), Cristina Airoldi (University of Milano-Bicocca), Aurora Maurizio (IRCCS Ospedale San Raffaele), Marta Chesi (Mayo Clinic in Arizona), Peter Leif Bergsagel (Mayo Clinic in Arizona), Nicola Clementi (Vita-Salute San Raffaele University, IRCCS Ospedale San Raffaele), Antonio Rosato (University of Padua, Istituto Oncologico Veneto), Matteo Bellone (IRCCS Ospedale San Raffaele)
Abstract: Smoldering multiple myeloma (SMM), which is in principle curable, may develop into life-threatening MM. Intestinal microbiota and gut-born T helper-17 (Th17) lymphocytes may contribute to this development, but the mechanisms are unclear. Here we demonstrate that administering the human commensal Prevotella melaninogenica to transgenic Vk*MYC mice that exhibit SMM-like phenotypes delays the evolution to full-blown MM. Mechanistically, P. melaninogenica increases the production of short-chain fatty acids (SCFA), thereby preventing the skewing of dendritic cells towards a pro-Th17 phenotype and subsequently accumulation of Th17 cells in the bone marrow of treated mice. P. melaninogenica or butyrate synergizes with anti-PD-L1 or anti-TIGIT to suppress myeloma progression by restraining Th17 cell expansion while inducing effector CD8+ T cells. P. melaninogenica also attenuates IL-17-mediated skin lesions that mimic anti-PD-L1-induced adverse events. Our results thus suggest that gut microbiota modulation or SCFAs administration may represent treatment options for patients affected by plasma cell dyscrasias. Smoldering multiple myeloma (SMM) may develop into life- threatening MM, with gut microbiota and Th17 possibly contributing to this progression via unknown mechanisms. Here the authors use a mouse SMM model, VkMYC mice, to show that treatments with butyrate or the commensal, Prevotella melaninogenica, suppress Th17 and cancer progression.