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Gut microbiota signatures are associated with toxicity to combined CTLA-4 and PD-1 blockade

Miles C Andrews1,2,3, Connie P M Duong4,5,6, Vancheswaran Gopalakrishnan1

  • 1Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.

Nature Medicine
|July 9, 2021
PubMed

Insights

Combined immune checkpoint blockade (CICB) shows clinical benefit but causes adverse events. Toxicity is linked to a diverse T-cell repertoire and specific gut bacteria, offering new therapeutic targets.

Area of Science:

  • Immunology
  • Oncology
  • Microbiome research

Background:

  • Combined immune checkpoint blockade (CICB) targeting CTLA-4 and PD-1 offers clinical benefits in various cancers.
  • However, CICB treatment is associated with a high incidence of immune-related adverse events (irAEs).
  • Understanding biomarkers and mechanisms of response and toxicity is crucial for optimizing CICB therapy.

Purpose of the Study:

  • To investigate biomarkers and mechanisms of response and toxicity in patients treated with CICB.
  • To correlate clinical outcomes with immune profiles, tumor genomics, and gut microbiome composition.
  • To explore potential therapeutic strategies for managing CICB-induced toxicity.

Main Methods:

  • Profiling of blood, tumor, and gut microbiome in 77 advanced melanoma patients receiving CICB.
  • Analysis of immune and genomic biomarkers associated with response to CICB.
  • Parallel studies in pre-clinical models to investigate mechanisms of toxicity.

Main Results:

  • Tumor biomarkers for response to CICB were consistent with those for immune checkpoint inhibitor (ICB) monotherapy.
  • CICB toxicity correlated with a more diverse peripheral T-cell repertoire.
  • Increased abundance of Bacteroides intestinalis in the gut microbiome was observed in patients experiencing toxicity.
  • Upregulation of mucosal IL-1β was noted in patient samples with colitis and in pre-clinical models.

Conclusions:

  • CICB response biomarkers are similar to ICB monotherapy.
  • Peripheral T-cell diversity and specific gut bacteria like Bacteroides intestinalis are associated with CICB toxicity.
  • Upregulation of IL-1β in the gut mucosa may play a role in CICB-induced colitis.
  • These findings suggest potential therapeutic targets for mitigating CICB-related adverse events.

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