%0 Journal Article
%A Marcos-Kovandzic, Laura
%A Avagliano, Michele
%A Ben Khelil, Myriam
%A Srikanthan, Janesa
%A Abdallah, Rim
%A Petrocelli, Valentina
%A Rengassamy, Jessica
%A Alfaro, Alexia
%A Bied, Mathilde
%A Fidelle, Marine
%A Ferrere, Gladys
%A Daillère, Romain
%A Arbab, Ahmadreza
%A Amine-Hneineh, Roula
%A Pages, Arnaud
%A Dartigues, Peggy
%A Ly, Pierre
%A Simon, Sylvain
%A Durand, Sylvère
%A Gottschlich, Adrian
%A Ginhoux, Florent
%A Blériot, Camille
%A Liu, Peng
%A Zhao, Liwei
%A Creusot, Laura
%A Rolhion, Nathalie
%A Derosa, Lisa
%A Kroemer, Guido
%A Menger, Laurie
%A Kobold, Sebastian
%A Castilla-Llorente, Cristina
%A Sokol, Harry
%A Casola, Stefano
%A Pasolli, Edoardo
%A Zitvogel, Laurence
%A Bigenwald, Camille
%T Gut Microbiota Modulation through Akkermansia spp. Supplementation Increases CAR T-cell Potency.
%J Cancer discovery
%V 15
%N 9
%@ 2159-8274
%C Philadelphia, Pa.
%I [Verlag nicht ermittelbar]
%M DKFZ-2025-01852
%P 1905 - 1926
%D 2025
%X 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.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.
%K Gastrointestinal Microbiome: immunology
%K Humans
%K Mice
%K Animals
%K Akkermansia: immunology
%K Immunotherapy, Adoptive: methods
%K Receptors, Aryl Hydrocarbon: metabolism
%K Receptors, Chimeric Antigen: immunology
%K Receptors, Chimeric Antigen: metabolism
%K Female
%K Lymphoma, B-Cell: therapy
%K Lymphoma, B-Cell: immunology
%K Lymphoma, B-Cell: microbiology
%K Dysbiosis
%K Male
%K Antigens, CD19: immunology
%K Receptors, Aryl Hydrocarbon (NLM Chemicals)
%K Receptors, Chimeric Antigen (NLM Chemicals)
%K Antigens, CD19 (NLM Chemicals)
%F PUB:(DE-HGF)16
%9 Journal Article
%$ pmid:40498998
%2 pmc:PMC12409280
%R 10.1158/2159-8290.CD-24-1230
%U https://inrepo02.dkfz.de/record/304439