Gut microbiota modulation through Akkermansia spp. supplementation increases CAR-T cell potency

IF 29.7 1区医学 Q1 ONCOLOGY

Cancer discovery Pub Date : 2025-06-11 DOI:10.1158/2159-8290.cd-24-1230

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 Daillere, Ahmadreza Arbab, Roula Amine-Hneineh, Arnaud Pages, Peggy Dartigues, Pierre Ly, Sylvain Simon, Sylvere Durand, Adrian Gottschlich, Florent Ginhoux, Camille Bleriot, Peng Liu, Liwei Zhao, Laura Creusot, Nathalie Rolhion, Guido Kroemer, Laurie Menger, Sebastian Kobold, Cristina Castilla-Llorente, Harry Sokol, Stefano Casola, Edoardo Pasolli, Laurence Zitvogel, Camille Bigenwald

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Abstract

This study investigates the clinical relevance of the gut microbiome at taxonomic and metabolic levels in anti-CD19 CAR-T cell therapy, both in patients and in a preclinical syngeneic tumor model. B cell lymphoma patients treated with CD19-CAR-T cells exhibited profound intestinal dysbiosis, exacerbated after CAR-T infusion. This dysbiosis was characterized by low bacterial richness, low sMAdCAM-1 and loss of Akkermansia species, associated with resistance to therapy. Mechanistically, oral Akkermansia massiliensis supplementation increased CAR-T cell infiltration into bone marrow, inverted the CD4/CD8 CAR-T ratio, favored Tc1 CD8+ T cell polarization and promoted 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 for the indole receptor, aryl hydrocarbon receptor (Ahr). Ahr-agonistic indoles alone failed to replicate the bacterium’s anticancer effects. These findings suggest Akkermansia supplementation could improve CAR-T cell potency in patients with intestinal Akkermansia deficiency.

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通过补充Akkermansia菌株调节肠道微生物群可增加CAR-T细胞效力

本研究在患者和临床前同基因肿瘤模型中探讨了肠道微生物组在抗cd19 CAR-T细胞治疗中的分类学和代谢水平的临床相关性。接受CD19-CAR-T细胞治疗的B细胞淋巴瘤患者表现出严重的肠道生态失调，CAR-T输注后加剧。这种生态失调的特点是细菌丰富度低，sMAdCAM-1低，Akkermansia物种的丧失，与治疗耐药性有关。从机制上说，口服马西莲增加了CAR-T细胞向骨髓的浸润，逆转了CD4/CD8 CAR-T比值，促进了Tc1 CD8+ T细胞极化，促进了色氨酸衍生的吲哚代谢产物的释放，从而更好地控制了肿瘤。当CAR-T细胞缺乏吲哚受体，芳烃受体（Ahr）时，补充Akkermansia的临床益处被取消。单独的ahr激动剂吲哚无法复制这种细菌的抗癌效果。这些发现表明补充Akkermansia可以提高肠道Akkermansia缺乏症患者的CAR-T细胞效力。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Cancer discovery ONCOLOGY-

CiteScore

22.90

自引率

1.40%

发文量

838

审稿时长

6-12 weeks

期刊介绍： Cancer Discovery publishes high-impact, peer-reviewed articles detailing significant advances in both research and clinical trials. Serving as a premier cancer information resource, the journal also features Review Articles, Perspectives, Commentaries, News stories, and Research Watch summaries to keep readers abreast of the latest findings in the field. Covering a wide range of topics, from laboratory research to clinical trials and epidemiologic studies, Cancer Discovery spans the entire spectrum of cancer research and medicine.