期刊
NATURE MEDICINE
卷 27, 期 8, 页码 1432-+出版社
NATURE PORTFOLIO
DOI: 10.1038/s41591-021-01406-6
关键词
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资金
- Cancer Prevention Research Institute of Texas
- Welch Foundation
- NIH/NCI [1 P50 CA221703-02, 1U54CA224070-03]
- American Cancer Society
- Melanoma Research Alliance [4022024]
- Cancer Fighters of Houston
- National Health and Medical Research Council of Australia CJ Martin Early Career Fellowship [1148680]
- National Institutes of Health T32 Training Grant [T32CA163185]
- CPRIT Research Training Program [RP170067]
- Fulbright France Commission Franco-Americaine
- John J. Kopchick Foundation
- Kimberley Clark Foundation by MD Anderson's Odyssey Fellowship Program
- Fonds de Recherche Quebec-Sante's (FRQS) Resident Physician Health Research Career Training Program [32667]
- National Institutes of Health [1R01CA219896-01A1, T32CA009599]
- MD Anderson Cancer Center [P30 CA016672]
- MSK Cancer Center Support Grant/Core Grant [P30 CA008748]
- EU
- Ligue contre le Cancer (equipe labelisee)
- Agence Nationale de la Recherche (ANR)-Projets blancs
- ANR
- ERA-Net for Research on Rare Diseases
- Association pour la recherche sur le cancer (ARC)
- Canceropole Ile-de-France
- Fondation de France
- Fondation pour la Recherche Medicale (FRM)
- Fondation Carrefour
- Institut National du Cancer (INCa)
- Inserm (HTE)
- ANR germanofrench
- LabEx Immuno-Oncology
- French Ministry of Health PIA2 [ANR-16-RHUS-0008]
- Swiss Bridge Foundation
- Seerave and Carrefour Foundation
- SIRIC Stratified Oncology Cell DNA Repair and Tumor Immune Elimination (SOCRATE)
- French Government under the 'Investissements d'avenir' (Investments for the Future) program [10-IAHU-03, NIH P30 CA008748]
- Region Provence Alpes Cote d'Azur
- European funding FEDER PRIMI
- Strategic Innovation Grant from the Division of Medical Oncology, University of Toronto
- American Association for Cancer Research Stand Up To Cancer [SU2C-AACR-IRG-19-17]
- MD Anderson Melanoma Moonshot Program
- Dr. Miriam and Sheldon G. Adelson Medical Research Foundation
- AIM at Melanoma Foundation
- Anne and John Mendelsohn Chair for Cancer Research, and philanthropic contributions
- National Health and Medical Research Council of Australia [1148680] Funding Source: NHMRC
The study showed that tumor-associated immune and genomic biomarkers of response to combined immune checkpoint blockade (CICB) in melanoma patients were similar to those of monotherapy, while toxicity from CICB was associated with a more diverse peripheral T-cell repertoire. Additionally, analysis of gut microbiota revealed a higher abundance of Bacteroides intestinalis in patients experiencing toxicity, along with an upregulation of the inflammatory factor IL-1 beta in colitis samples.
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-1 beta in patient samples of colitis and in pre-clinical models. Together, these data offer potential new therapeutic angles for targeting toxicity to CICB. Clinical benefit or intestinal toxicity resulting from combined immune checkpoint blockade in patients with melanoma associates with prevalent commensal bacteria and can be decoupled by IL-1R inhibition.
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