Gut Microbiota Modulation through <i>Akkermansia</i> spp <i>.</i> Supplementation Increases CAR T-cell Potency
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 Pagès, 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
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.