Gut microbiota signatures are associated with toxicity to combined CTLA-4 and PD-1 blockade.
Journal
Nature medicine
ISSN: 1546-170X
Titre abrégé: Nat Med
Pays: United States
ID NLM: 9502015
Informations de publication
Date de publication:
08 2021
08 2021
Historique:
received:
01
12
2020
accepted:
25
05
2021
pubmed:
10
7
2021
medline:
18
9
2021
entrez:
9
7
2021
Statut:
ppublish
Résumé
Treatment with combined immune checkpoint blockade (CICB) targeting CTLA-4 and PD-1 is associated with clinical benefit across tumor types, but also a high rate of immune-related adverse events. Insights into biomarkers and mechanisms of response and toxicity to CICB are needed. To address this, we profiled the blood, tumor and gut microbiome of 77 patients with advanced melanoma treated with CICB, with a high rate of any ≥grade 3 immune-related adverse events (49%) with parallel studies in pre-clinical models. Tumor-associated immune and genomic biomarkers of response to CICB were similar to those identified for ICB monotherapy, and toxicity from CICB was associated with a more diverse peripheral T-cell repertoire. Profiling of gut microbiota demonstrated a significantly higher abundance of Bacteroides intestinalis in patients with toxicity, with upregulation of mucosal IL-1β in patient samples of colitis and in pre-clinical models. Together, these data offer potential new therapeutic angles for targeting toxicity to CICB.
Identifiants
pubmed: 34239137
doi: 10.1038/s41591-021-01406-6
pii: 10.1038/s41591-021-01406-6
doi:
Substances chimiques
CTLA-4 Antigen
0
CTLA4 protein, human
0
Interleukin-1beta
0
PDCD1 protein, human
0
Programmed Cell Death 1 Receptor
0
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1432-1441Subventions
Organisme : NCI NIH HHS
ID : T32 CA163185
Pays : United States
Organisme : NCI NIH HHS
ID : P30 CA016672
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA219896
Pays : United States
Organisme : NCI NIH HHS
ID : P30 CA008748
Pays : United States
Organisme : NCI NIH HHS
ID : U54 CA224070
Pays : United States
Organisme : NCI NIH HHS
ID : P50 CA221703
Pays : United States
Commentaires et corrections
Type : CommentIn
Informations de copyright
© 2021. The Author(s), under exclusive licence to Springer Nature America, Inc.
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