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

<div>Abstract<p>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 <i>Akkermansia</i> species, associated with resistance to therapy. Mechanistically, oral <i>Akkermansia massiliensis</i> supplementation increased CAR T-cell infiltration into the bone marrow, inverted the CD4/CD8 CAR T-cell ratio, favored Tc1 CD8<sup>+</sup> T-cell polarization, and promoted the release of tryptophan-derived indole metabolites, leading to better tumor control. The clinical benefit of <i>Akkermansia</i> 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 <i>Akkermansia</i> supplementation could improve CAR T-cell potency in patients with intestinal <i>Akkermansia</i> deficiency.</p>Significance:<p>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 <i>A. massiliensis</i> supplementation induces CAR T-cell niching and Tc1 differentiation in the bone marrow, promoting tumor control in an <i>AhR-</i>dependent manner.</p></div>