Gut Microbiota Modulation through Akkermansia spp . Supplementation Increases CAR T-cell Potency
Year: 2025
Type: article
Abstract: This study investigates the clinical relevance of the gut microbiome at taxonomic and metabolic levels in anti-CD19 chimeric antigen receptor (CAR) T-cell therapy, both in patients and in a preclinical syngeneic tumor model. Patients with B-cell lymphoma treated with CD19 CAR T cells exhibited profound intestinal dysbiosis, exacerbated after CAR T-cell infusion. This dysbiosis was characterized by low bacterial richness, low soluble MAdCAM-1, and loss of Akkermansia species, associated with resistance to therapy. Mechanistically, oral Akkermansia massiliensis supplementation increased CAR T-cell infiltration into the bone marrow, inverted the CD4/CD8 CAR T-cell ratio, favored Tc1 CD8+ T-cell polarization, and promoted the release of tryptophan-derived indole metabolites, leading to better tumor control. The clinical benefit of Akkermansia spp. supplementation was abolished when CAR T cells were genetically deficient in the indole receptor, aryl hydrocarbon receptor (AhR). AhR-agonistic indoles alone failed to replicate the bacterium's anticancer effects. These findings suggest that Akkermansia supplementation could improve CAR T-cell potency in patients with intestinal Akkermansia deficiency. SIGNIFICANCE: B-cell lymphoma patients treated with CAR T cells harbor major gut microbiota perturbations and related metabolism that restrain CAR T-cell therapy. Reprogramming the gut microbiota ecosystem by oral A. massiliensis supplementation induces CAR T-cell niching and Tc1 differentiation in the bone marrow, promoting tumor control in an AhR-dependent manner.
Source: Cancer Discovery
Authors: Laura Marcos-Kovandzic, Michele Avagliano, Myriam Ben Khelil, Janesa Srikanthan, Rim Abdallah, Valentina Petrocelli, Jessica Rengassamy, Alexia Alfaro, Mathilde Bied, Marine Fidelle, Gladys Ferrere, Romain Daillère, Ahmadreza Arbab, Roula Amine-Hneineh, Arnaud Pages, Peggy Dartigues, Pierre Ly, Sylvain Simon, Sylvère Durand, Adrian Gottschlich, Florent Ginhoux, Camille Blériot, Peng Liu, Liwei Zhao, Laura Creusot, Nathalie Rolhion, Lisa Derosa, Guido Kroemer, Laurie Menger, Sebastian Kobold, Cristina Castilla-Llorente, Harry Sokol, Stefano Casola, Edoardo Pasolli, Laurence Zitvogel, Camille Bigenwald
Institutions: Inserm, Université Paris-Saclay, Institut Gustave Roussy, University of Naples Federico II, IFOM, Centre National de la Recherche Scientifique, Analyse moléculaire, modélisation et imagerie de la maladie cancéreuse, Centre de recherche en Epidémiologie et Santé des Populations, Fred Hutch Cancer Center, Institut Universitaire de France, Université Paris Cité, Sorbonne Université, Centre de Recherche des Cordeliers, LMU Klinikum, German Center for Lung Research, Deutsches Konsortium für Translationale Krebsforschung, Ludwig-Maximilians-Universität München, Agency for Science, Technology and Research, Singapore Immunology Network, Assistance Publique – Hôpitaux de Paris, Hôpital Saint-Antoine, Fédération Hospitalo-Universitaire, Paris Center for Microbiome Medicine, Centre de Recherche Saint-Antoine, Institut Curie, University of Milan
Language: English
Topic: CAR-T cell therapy research
Subfield: Oncology
Field: Medicine
Domain: Health Sciences
Open Access status: hybrid
Funders: Gilead Sciences, Association pour la Recherche sur le Cancer, Università degli Studi di Milano, Seerave Foundation, Equipex, European Commission, Deutsche Forschungsgemeinschaft, Agence Nationale de la Recherche, Fondation pour la Recherche Médicale, Ligue Contre le Cancer, Institut Universitaire de France, Associazione Italiana per la Ricerca sul Cancro, Institut National Du Cancer, Servier, Université de Paris, Institut Servier, HORIZON EUROPE Framework Programme, Labex Immuno-Oncology, HORIZON EUROPE European Research Council
Awards: G1056382719, G1190173965, G1238255649, Next-generation phenotypic screening for oncological applications, G1835096447, G1931939986, G1963894250, Biomarkers affecting the transition from cardiovascular disease to lung cancer: towards stratified interception., Gut OncoMicrobiome Signatures (GOMS) associated with cancer incidence, prognosis and prediction of treatment response., G3803576849, G4053556010, G434337789, G4656594441, G4707887143, Microbiota-centered interventions to solve antibiotics-induced primary resistance to immune checkpoint inhibitors, Immunogenic cell death (ICD) in the cancer-immune dialogue, Centre National de Médecine de Précision en Oncologie, Training Network for Optimizing Adoptive T cell Therapy of Cancer, G7041469554, G7255431040, G7612322874, G8131733946, G82931992, Université de Paris
OpenAlex ID: W4411201413