A gut microbial signature for combination immune checkpoint blockade across cancer types

Gunjur, A; PALMER, J; Shao, Y; Rozday, T; Klein, O; Mu, A; Haak, BW; Markman, B; Kee, D; Carlino, MS; Underhill, C; Frentzas, S; Michael, M; Gao, B; Cebon, J; Behren, A; Adams, DJ; Lawley, TD

Author(s): Gunjur, A; PALMER, J; Shao, Y; Rozday, T; Klein, O; Mu, A; Haak, BW; Markman, B; Kee, D; Carlino, MS; Underhill, C; Frentzas, S; Michael, M; Gao, B; Cebon, J; Behren, A; Adams, DJ; Lawley, TD;
Details: Publication Year 2024-03-01,Volume 30,Issue #3,Page 797-809
Journal Title: Nature Medicine
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
Research Division(s): Cancer Biology And Stem Cells
PubMed ID: 38429524
Publisher's Version: https://doi.org/10.1038/s41591-024-02823-z
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.

Creation Date: 2024-03-04 01:53:14

Last Modified: 2024-06-28 03:08:41