2. Academic Validation
  3. Microbiome modulation uncouples efficacy and toxicity induced by immune checkpoint blockade in mouse multiple myeloma

Microbiome modulation uncouples efficacy and toxicity induced by immune checkpoint blockade in mouse multiple myeloma

  • Nat Commun. 2025 Nov 24;16(1):10384. doi: 10.1038/s41467-025-65312-y.
Laura Lucia Cogrossi 1 2,  Anna Policastro 1,  Paola Zordan 1,  Matteo Grioni 1,  Anna Tosi 3,  Nathalie Rizzo 4,  Benedetta Mattorre 1,  Marco Lorenzoni 1,  Greta Meregalli 1,  Sofia Sisti 2 5,  Francesca Sanvito 4,  Alessandro Palmioli 6 7,  Cristina Airoldi 6,  Aurora Maurizio 8,  Marta Chesi 9,  Leif Bergsagel 9,  Nicola Clementi 2 5,  Antonio Rosato 3 10,  Matteo Bellone 11
Affiliations

Affiliations

  • 1 Cellular immunology Unit, Division of Immunology, Transplantation and Infectious Diseases, IRCCS Ospedale San Raffaele, Milan, Italy.
  • 2 Vita-Salute San Raffaele University, Milan, Italy.
  • 3 Immunology and Molecular Oncology Diagnostics, Istituto Oncologico, Veneto, Padua, Italy.
  • 4 Pathology and histology department, IRCCS Ospedale San Raffaele, Milan, Italy.
  • 5 Laboratory of Microbiology, IRCCS Ospedale San Raffaele, Milan, Italy.
  • 6 Università degli studi Milano-Bicocca, Milan, Italy.
  • 7 BioOrg NMR Lab, Department of Biotechnology and Biosciences, University of Milano-Bicocca, Milan, Italy.
  • 8 Center for Omics Sciences, IRCCS San Raffaele Scientific Institute, Milan, Italy.
  • 9 Mayo Clinic, Scottsdale, Arizona, USA.
  • 10 Department of Surgery, Oncology and Gastroenterology (DiSCOG), University of Padua, Padua, Italy.
  • 11 Cellular immunology Unit, Division of Immunology, Transplantation and Infectious Diseases, IRCCS Ospedale San Raffaele, Milan, Italy. [email protected].
PMID: 41285849 DOI: 10.1038/s41467-025-65312-y
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.

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