1. Longitudinal analysis of the gut microbiota during anti-PD-1 therapy reveals stable microbial features of response in melanoma patients.
- Author
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Macandog ADG, Catozzi C, Capone M, Nabinejad A, Nanaware PP, Liu S, Vinjamuri S, Stunnenberg JA, Galiè S, Jodice MG, Montani F, Armanini F, Cassano E, Madonna G, Mallardo D, Mazzi B, Pece S, Tagliamonte M, Vanella V, Barberis M, Ferrucci PF, Blank CU, Bouvier M, Andrews MC, Xu X, Santambrogio L, Segata N, Buonaguro L, Cocorocchio E, Ascierto PA, Manzo T, and Nezi L
- Abstract
Immune checkpoint inhibitors (ICIs) improve outcomes in advanced melanoma, but many patients are refractory or experience relapse. The gut microbiota modulates antitumor responses. However, inconsistent baseline predictors point to heterogeneity in responses and inadequacy of cross-sectional data. We followed patients with unresectable melanoma from baseline and during anti-PD-1 therapy, collecting fecal and blood samples that were surveyed for changes in the gut microbiota and immune markers. Varying patient responses were linked to different gut microbiota dynamics during ICI treatment. We select complete responders by their stable microbiota functions and validate them using multiple external cohorts and experimentally. We identify major histocompatibility complex class I (MHC class I)-restricted peptides derived from flagellin-related genes of Lachnospiraceae (FLach) as structural homologs of tumor-associated antigens, detect FLach-reactive CD8
+ T cells in complete responders before ICI therapy, and demonstrate that FLach peptides improve antitumor immunity. These findings highlight the prognostic value of microbial functions and therapeutic potential of tumor-mimicking microbial peptides., Competing Interests: Declaration of interests L.N., T.M., P.A.A., and A.D.G.M. are named co-inventors on a patent application relating to this work (EP n. 24164184.4 “Flagellin-related peptides and uses”). M.C.A. reports advisory board participation, honoraria, or research funds to institutions from MSD Australia, BMS Australia, and Pierre Fabre Australia and is a named co-inventor on a patent application relating to Methods and compositions for treating cancer (WO2020106983A1), all unrelated to this work. P.A.A. reports grants or contracts from Bristol Myers Squibb, Roche-Genentech, Pfizer, and Sanofi; consulting fees from Bristol Myers Squibb, Roche-Genentech, Merck Sharp & Dohme, Novartis, Merck Serono, Pierre Fabre, Sun Pharma, Sanofi, Sandoz, Italfarmaco, Nektar, Pfizer, Lunaphore, Medicenna, Bio-Al Health, ValoTx, Replimmune, and Bayer; support for attending meetings and/or travel from Pfizer, Bio-Al Health, and Replimmune; and participating on a data safety monitoring board or advisory board for Bristol Myers Squibb, Roche-Genentech, Merck Sharp & Dohme, Novartis, AstraZeneca, Boehringer Ingelheim, Eisai, Regeneron, Daiichi Sankyo, Oncosec, Nouscom, Seagen, iTeos, and Erasca. L.N. reports research funds from BMS Europe unrelated to this work., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)- Published
- 2024
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