Bile acids regulate MAdCAM-1 expression to link the gut microbiota to cancer immunosurveillance

ABSTRACT

In a recent paper in Science, Fidelle et al. unravel a gut immune checkpoint that is subverted by antibiotic treatment. Post-antibiotic dysbiosis of the ileum causes an increase in bile acids that downregulate MAdCAM−1, thereby triggering the exodus of immunosuppressive T cells from gut-associated lymphoid tissues toward tumors.

KEYWORDS:

• Cancer immunotherapy
• microbiota
• immunosuppression
• MAdCAM-1
• bile acids
• Enterocloster
• gut

Acknowledgments

MF is supported by the Seerave Foundation and the European Union’s Horizon Europe research and innovation programme under grant agreement number 101095604 - GAP-101095604 -[project acronym: PREVALUNG-EU, project title: Personalized lung cancer risk assessment leading to stratified Interception]. This work was supported by SEERAVE Foundation, European Union Horizon 2020:Project Number: 825410 and Project Acronym: ONCOBIOME, Institut National du Cancer (INCa), ANR Ileobiome - 19-CE15-0029-01, ANR RHU5 “ANR-21-5 RHUS-0017” IMMUNOLIFE”, MAdCAM INCA_ 16698, Ligue contre le cancer, LABEX OncoImmunology, la direction generale de l’offre de soins (DGOS), Universite Paris-Sud, SIRIC SOCRATE (INCa/DGOS/INSERM 6043), and PACRI network. Ai-L is supported by the ANR RHU5 “ANR-21-5 RHUS-0017” IMMUNOLIFE”. LZ and GK are supported by the Ligue contre le Cancer (équipes labellisées, Program “Equipe labelisée LIGUE”; no. EL2016.LNCC (VT/PLP)); Agence Nationale de la Recherche (ANR) – Projets blancs; ANR under the frame of E-Rare-2, the ERA-Net for Research on Rare Diseases; AMMICa US23/CNRS UMS3655; Association pour la recherche sur le cancer (ARC); Association “Le Cancer du Sein, Parlons-en!”; Cancéropôle Ile-de-France; Chancelerie des universités de Paris (Legs Poix), Fondation pour la Recherche Médicale (FRM); a donation by Elior; European Research Area Network on Cardiovascular Diseases (ERA-CVD, MINOTAUR); Gustave Roussy Odyssea, the European Union Horizon 2020 Project Oncobiome; Fondation Carrefour; INCa; Inserm (HTE); Institut Universitaire de France; LeDucq Foundation; the LabEx Immuno-Oncology (ANR-18-IDEX-0001); the RHU Torino Lumière; the Seerave Foundation; the SIRIC Stratified Oncology Cell DNA Repair and Tumor Immune Elimination (SOCRATE); and the SIRIC Cancer Research and Personalized Medicine (CARPEM).

Disclosure statement

LZ is a cofounder of everImmune, and holds patents covering the treatment of cancer and the therapeutic manipulation of the microbiota. LZ has held research contracts with Glaxo Smyth Kline, Incyte, Lytix, Kaleido, Pileje, Transgene, 9 m, Tusk Pharma, Merus, Roche and Innovate Pharma, and now has current research support from Biomérieux, Daiichi Sankyo, everImmune, Pilege, and 9 meters. LZ is in the SAB of Hookipa. LZ was on the Board of Directors of Transgene. GK has been holding research contracts with Daiichi Sankyo, Eleor, Kaleido, Lytix Pharma, PharmaMar, Osasuna Therapeutics, Samsara Therapeutics, Sanofi, Sotio, Tollys, Vascage and Vasculox/Tioma. GK has been consulting for Reithera. GK is on the Board of Directors of the Bristol Myers Squibb Foundation France. GK is a scientific co-founder of everImmune, Osasuna Therapeutics, Samsara Therapeutics and Therafast Bio. GK is the inventor of patents covering therapeutic targeting of aging, cancer, cystic fibrosis and metabolic disorders. GK’s brother, Romano Kroemer, was an employee of Sanofi and now consults for Boehringer-Ingelheim. The funders had no role in the design of the study; in the writing of the manuscript, or in the decision to publish the results.

Data availability statement

All data that led to the conclusions in this manuscript have been referenced and all sources have been described.

Additional information

Funding

The work was supported by the Agence Nationale de la Recherche [Projets blancs]; Association pour la Recherche sur le Cancer Cancéropôle Ile de France Fondation Leducq Fondation pour la Recherche Médicale Institut National Du Cancer Institut Universitaire de France Ligue Contre le Cancer [EL2016.LNCC (VT/PLP)]; European Research Area Network on Cardiovascular Diseases (ERA-CVD, MINOTAUR) Gustave Roussy Odyssea the European Union Horizon 2020 Project Oncobiome Fondation Carrefour Inserm (HTE) the LabEx Immuno-Oncology [ANR-18-IDEX-0001]; the RHU Torino Lumière a donation by Elior Chancelerie des universités de Paris (Legs Poix) Association “Le Cancer du Sein, Parlons-en!” AMMICa US23/CNRS UMS3655 ANR under the frame of E-Rare-2, the ERA-Net for Research on Rare Diseases Agence Nationale de la Recherche (ANR) – Projets blancs the SIRIC Cancer Research and Personalized Medicine (CARPEM) Equipe labelisée LIGUE [EL2016.LNCC (VT/PLP)]; Immunolife [ANR-21-5 RHUS-0017]; the SIRIC Stratified Oncology Cell DNA Repair and Tumor Immune Elimination (SOCRATE) Seerave Foundation.