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

Laura Lucia Cogrossi, Anna Policastro, Paola Zordan, Matteo Grioni, Anna Tosi, Nathalie Rizzo, Benedetta Mattorre, Marco Lorenzoni, Greta Meregalli, Sofia Sisti, Francesca Sanvito, Alessandro Palmioli, Cristina Airoldi, Aurora Maurizio, Marta Chesi, Leif Bergsagel, Nicola Clementi, Antonio Rosato and Matteo Bellone ()
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Laura Lucia Cogrossi: IRCCS Ospedale San Raffaele, Cellular immunology Unit, Division of Immunology, Transplantation and Infectious Diseases
Anna Policastro: IRCCS Ospedale San Raffaele, Cellular immunology Unit, Division of Immunology, Transplantation and Infectious Diseases
Paola Zordan: IRCCS Ospedale San Raffaele, Cellular immunology Unit, Division of Immunology, Transplantation and Infectious Diseases
Matteo Grioni: IRCCS Ospedale San Raffaele, Cellular immunology Unit, Division of Immunology, Transplantation and Infectious Diseases
Anna Tosi: Istituto Oncologico, Immunology and Molecular Oncology Diagnostics
Nathalie Rizzo: IRCCS Ospedale San Raffaele, Pathology and histology department
Benedetta Mattorre: IRCCS Ospedale San Raffaele, Cellular immunology Unit, Division of Immunology, Transplantation and Infectious Diseases
Marco Lorenzoni: IRCCS Ospedale San Raffaele, Cellular immunology Unit, Division of Immunology, Transplantation and Infectious Diseases
Greta Meregalli: IRCCS Ospedale San Raffaele, Cellular immunology Unit, Division of Immunology, Transplantation and Infectious Diseases
Sofia Sisti: Vita-Salute San Raffaele University
Francesca Sanvito: IRCCS Ospedale San Raffaele, Pathology and histology department
Alessandro Palmioli: Università degli studi Milano-Bicocca
Cristina Airoldi: Università degli studi Milano-Bicocca
Aurora Maurizio: IRCCS San Raffaele Scientific Institute, Center for Omics Sciences
Marta Chesi: Mayo Clinic
Leif Bergsagel: Mayo Clinic
Nicola Clementi: Vita-Salute San Raffaele University
Antonio Rosato: Istituto Oncologico, Immunology and Molecular Oncology Diagnostics
Matteo Bellone: IRCCS Ospedale San Raffaele, Cellular immunology Unit, Division of Immunology, Transplantation and Infectious Diseases

Nature Communications, 2025, vol. 16, issue 1, 1-16

Abstract: 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.

Date: 2025
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DOI: 10.1038/s41467-025-65312-y

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