A gut microbial signature for combination immune checkpoint blockade across cancer types
Details
Publication Year 2024-03,Volume 30,Issue #3,Page 797-809
Journal Title
Nature Medicine
Publication Type
Research article
Abstract
Immune checkpoint blockade (ICB) targeting programmed cell death protein 1 (PD-1) and cytotoxic T lymphocyte protein 4 (CTLA-4) can induce remarkable, yet unpredictable, responses across a variety of cancers. Studies suggest that there is a relationship between a cancer patient's gut microbiota composition and clinical response to ICB; however, defining microbiome-based biomarkers that generalize across cohorts has been challenging. This may relate to previous efforts quantifying microbiota to species (or higher taxonomic rank) abundances, whereas microbial functions are often strain specific. Here, we performed deep shotgun metagenomic sequencing of baseline fecal samples from a unique, richly annotated phase 2 trial cohort of patients with diverse rare cancers treated with combination ICB (n = 106 discovery cohort). We demonstrate that strain-resolved microbial abundances improve machine learning predictions of ICB response and 12-month progression-free survival relative to models built using species-rank quantifications or comprehensive pretreatment clinical factors. Through a meta-analysis of gut metagenomes from a further six comparable studies (n = 364 validation cohort), we found cross-cancer (and cross-country) validity of strain-response signatures, but only when the training and test cohorts used concordant ICB regimens (anti-PD-1 monotherapy or combination anti-PD-1 plus anti-CTLA-4). This suggests that future development of gut microbiome diagnostics or therapeutics should be tailored according to ICB treatment regimen rather than according to cancer type.
Publisher
Springer Nature
Keywords
Humans; Immune Checkpoint Inhibitors/therapeutic use; *Gastrointestinal Microbiome/genetics; *Neoplasms/drug therapy/genetics
Department(s)
Medical Oncology
Open Access at Publisher's Site
https://doi.org/10.1038/s41591-024-02823-z
Terms of Use/Rights Notice
Refer to copyright notice on published article.


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