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<p>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 <i>Prevotella melaninogenica</i> to transgenic Vk*MYC mice that exhibit SMM-like phenotypes delays the evolution to full-blown MM. Mechanistically, <i>P. melaninogenica</i> 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. <i>P. melaninogenica</i> 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. <i>P. melaninogenica</i> 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.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年11月24日

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  • 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,
  • Matteo Bellone

摘要

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.