The immunotoxicity, but not anti-tumor efficacy, of anti-CD40 and anti-CD137 immunotherapies is dependent on the gut microbiota

Stephen J. Blake, Jane James, Feargal J. Ryan, Jose Caparros-Martin, Georgina L. Eden, Yee C. Tee, John R. Salamon, Saoirse C. Benson, Damon J. Tumes, Anastasia Sribnaia, Natalie E. Stevens, John W. Finnie, Hiroki Kobayashi, Deborah L. White, Steve L. Wesselingh, Fergal O'Gara, Miriam A. Lynn, David J. Lynn

Research output: Contribution to journalArticlepeer-review

10 Citations (Scopus)


Immune agonist antibodies (IAAs) are promising immunotherapies that target co-stimulatory receptors to induce potent anti-tumor immune responses, particularly when combined with checkpoint inhibitors. Unfortunately, their clinical translation is hampered by serious dose-limiting, immune-mediated toxicities, including high-grade and sometimes fatal liver damage, cytokine release syndrome (CRS), and colitis. We show that the immunotoxicity, induced by the IAAs anti-CD40 and anti-CD137, is dependent on the gut microbiota. Germ-free or antibiotic-treated mice have significantly reduced colitis, CRS, and liver damage following IAA treatment compared with conventional mice or germ-free mice recolonized via fecal microbiota transplant. MyD88 signaling is required for IAA-induced CRS and for anti-CD137-induced, but not anti-CD40-induced, liver damage. Importantly, antibiotic treatment does not impair IAA anti-tumor efficacy, alone or in combination with anti-PD1. Our results suggest that microbiota-targeted therapies could overcome the toxicity induced by IAAs without impairing their anti-tumor activity.

Original languageEnglish
Article number100464
JournalCell Reports Medicine
Issue number12
Publication statusPublished or Issued - 21 Dec 2021


  • anti-CD137
  • anti-CD40
  • cytokine release syndrome
  • gut microbiota
  • immune agonist antibody
  • immunotherapy
  • liver damage

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this