Microbiome modulation uncouples efficacy and toxicity induced by immune checkpoint blockade in mouse multiple myeloma
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<sup>+</sup> 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.
Authors
- P. Leif Bergsagel (ORCID: https://orcid.org/0000-0003-1523-7388)
- Marta Chesi (ORCID: https://orcid.org/0000-0002-4024-8225)
- Nicola Clementi (ORCID: https://orcid.org/0000-0002-1822-9861)
- Matteo Bellone (ORCID: https://orcid.org/0000-0002-2586-2569)
- Benedetta Mattorre
- Cristina Airoldi (ORCID: https://orcid.org/0000-0002-3670-6262)
- Francesca Sanvito (ORCID: https://orcid.org/0000-0002-4046-8420)
- Sofia Sisti (ORCID: https://orcid.org/0000-0002-8006-7218)
- Aurora Maurizio (ORCID: https://orcid.org/0000-0002-7194-4637)
- Paola Zordan (ORCID: https://orcid.org/0000-0001-6915-5535)
- Antonio Rosato (ORCID: https://orcid.org/0000-0002-5263-8386)
- Marco Lorenzoni (ORCID: https://orcid.org/0000-0002-3040-0633)
- Alessandro Palmioli (ORCID: https://orcid.org/0000-0002-5287-1663)
- Matteo Grioni (ORCID: https://orcid.org/0000-0002-9930-042X)
- Laura Lucia Cogrossi (ORCID: https://orcid.org/0000-0002-7479-4320)
- Anna Tosi (ORCID: https://orcid.org/0000-0002-4890-0169)
- Anna Policastro (ORCID: https://orcid.org/0009-0009-2388-6098)
- Greta Meregalli
- N. Rizzo (ORCID: https://orcid.org/0000-0002-5414-2464)
Institutions
- University of Padua (IT)
- Vita-Salute San Raffaele University (IT)
- Istituto Oncologico Veneto (IT)
- Mayo Clinic in Arizona (US)
- IRCCS Ospedale San Raffaele (IT)
- Istituti di Ricovero e Cura a Carattere Scientifico (IT)
- Istituto di Ricovero e Cura a Carattere Scientifico San Raffaele (IT)
- University of Milano-Bicocca (IT)
Publication Details
- Journal
- Nature Communications
- Published
- 2025-11-24
- DOI
- https://doi.org/10.1038/s41467-025-65312-y
- Citations
- 1
- Primary Topic
- Gut microbiota and health
- Type
- article
- Field-Weighted Citation Impact
- 0.81
Funders
- Cancer Research Institute
- Associazione Italiana per la Ricerca sul Cancro