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

  • Cancer Discov. 2025 Jun 11. doi: 10.1158/2159-8290.CD-24-1230.
Laura Marcos-Kovandzic  1 ,  Michele Avagliano  2 ,  Myriam Ben Khelil  3 ,  Janesa Srikanthan  1 ,  Rim Abdallah  4 ,  Valentina Petrocelli  5 ,  Jessica Rengassamy  1 ,  Alexia Alfaro  3 ,  Mathilde Bied  6 ,  Marine Fidelle  3 ,  Gladys Ferrere  6 ,  Romain Daillere  3 ,  Ahmadreza Arbab  3 ,  Roula Amine-Hneineh  1 ,  Arnaud Pages  3 ,  Peggy Dartigues  3 ,  Pierre Ly  7 ,  Sylvain Simon  8 ,  Sylvere Durand  9 ,  Adrian Gottschlich  10 ,  Florent Ginhoux  11 ,  Camille Bleriot  3 ,  Peng Liu  3 ,  Liwei Zhao  6 ,  Laura Creusot  12 ,  Nathalie Rolhion  12 ,  Lisa Derosa  7 ,  Guido Kroemer  13 ,  Laurie Menger  14 ,  Sebastian Kobold  10 ,  Cristina Castilla-Llorente  15 ,  Harry Sokol  16 ,  Stefano Casola  17 ,  Edoardo Pasolli  2 ,  Laurence Zitvogel  3 ,  Camille Bigenwald  3
Affiliations
  • 1. Institut Gustave Roussy, Villejuif, île-de-france, France.
  • 2. University of Naples Federico II, Italy.
  • 3. Institut Gustave Roussy, Villejuif, France.
  • 4. Inserm, Paris, France.
  • 5. FIRC Institute of Molecular Oncology, Milan, Italy.
  • 6. Institut Gustave Roussy, France.
  • 7. Gustave Roussy Cancer Campus (GRCC), Villejuif, France.
  • 8. fred hutchinson cancer center, France.
  • 9. INSERM U1138, Villejuif, France.
  • 10. LMU Klinikum, Munich, Germany.
  • 11. Singapore Immunology Network Agency for Science, Technology, and Research, Singapore, Singapore.
  • 12. Centre de Recherche Saint-Antoine, France.
  • 13. Gustave Roussy Cancer Campus, Paris, France.
  • 14. Institute Curie, Paris, France.
  • 15. Institut Gustave Roussy, French Guiana.
  • 16. Hôpital Saint-Antoine, Paris, France.
  • 17. IFOM ETS-The AIRC Institute of Molecular Oncology, Milano, Italy, Milano, Italy.
PMID: 40498998 DOI: 10.1158/2159-8290.CD-24-1230
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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