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Longitudinal gut microbiome changes in immune checkpoint blockade-treated advanced melanoma
Johannes R. Björk (University Medical Center Groningen, University of Groningen), Laura A. Bolte (University Medical Center Groningen, University of Groningen), Andrew Maltez Thomas (University of Trento), Karla A. Lee (King's College London), Niccolò Rossi (King's College London), Thijs T. Wind (University Medical Center Groningen, University of Groningen), Lotte M. Smit (University Medical Center Groningen, University of Groningen), Federica Armanini (University of Trento), Francesco Asnicar (University of Trento), Aitor Blanco‐Míguez (University of Trento), Ruth Board (Lancashire Teaching Hospitals NHS Foundation Trust), Neus Calbet‐Llopart (Instituto de Salud Carlos III, Hospital Clínic de Barcelona), Lisa Derosa (Inserm, Université Paris-Saclay), Nathalie S. Dhomen (University of Manchester), Kelly M. Brooks (University of Manchester), Mark Harland (University of Leeds), Mark Harries (Guy's Hospital, Guy's and St Thomas' NHS Foundation Trust), Paul C. Lorigan (University of Manchester, The Christie NHS Foundation Trust), Paolo Manghi (University of Trento), Richard Marais (University of Manchester, Cancer Research UK Manchester Institute), Julia Newton‐Bishop (University of Leeds), Luigi Nezi (European Institute of Oncology), Federica Pinto (University of Trento), Míriam Potrony (Instituto de Salud Carlos III, Hospital Clínic de Barcelona), Susana Puig (Instituto de Salud Carlos III, Hospital Clínic de Barcelona), Patricio Serra-Bellver (The Christie NHS Foundation Trust), Heather May Shaw (Mount Vernon Cancer Centre), Sabrina Tamburini (European Institute of Oncology), Sara Valpione (University of Manchester, The Christie NHS Foundation Trust), Levi Waldron (City University of New York, University of Trento), Laurence Zitvogel (Inserm, Université Paris-Saclay), Moreno Zolfo (University of Trento), Elisabeth G.E. de Vries (University Medical Center Groningen, University of Groningen), Paul Nathan (Mount Vernon Cancer Centre, Hospital Clínic de Barcelona), Rudolf S.N. Fehrmann (University Medical Center Groningen, University of Groningen), Tim D. Spector (King's College London), Veronique A. Bataille (King's College London, Hemel Hempstead Hospital), Nicola Segata (University of Trento, European Institute of Oncology), Geke A.P. Hospers (University Medical Center Groningen, University of Groningen), Rinse Karel Weersma (University Medical Center Groningen, University of Groningen)
Résumé : Abstract Multiple clinical trials targeting the gut microbiome are being conducted to optimize treatment outcomes for immune checkpoint blockade (ICB). To improve the success of these interventions, understanding gut microbiome changes during ICB is urgently needed. Here through longitudinal microbiome profiling of 175 patients treated with ICB for advanced melanoma, we show that several microbial species-level genome bins (SGBs) and pathways exhibit distinct patterns from baseline in patients achieving progression-free survival (PFS) of 12 months or longer (PFS ≥12) versus patients with PFS shorter than 12 months (PFS <12). Out of 99 SGBs that could discriminate between these two groups, 20 were differentially abundant only at baseline, while 42 were differentially abundant only after treatment initiation. We identify five and four SGBs that had consistently higher abundances in patients with PFS ≥12 and <12 months, respectively. Constructing a log ratio of these SGBs, we find an association with overall survival. Finally, we find different microbial dynamics in different clinical contexts including the type of ICB regimen, development of immune-related adverse events and concomitant medication use. Insights into the longitudinal dynamics of the gut microbiome in association with host factors and treatment regimens will be critical for guiding rational microbiome-targeted therapies aimed at enhancing ICB efficacy.