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
  • 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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