Microbiota-associated immunotherapy resistance caused by deficient PD-L2 - RGMb signaling

ABSTRACT

In a recent paper in Nature, Park et al. propose a mechanism through which intestinal dysbiosis compromises the efficacy of immunotherapy targeting the PD-L1/PD−1 interaction. Dysbiosis may upregulate a pair of checkpoint molecules, i.e. PD-L2 interacting with RGMb. Antibodies targeting PD-L2/RGMb can restore responses to PD−1 blockade in the context of dysbiosis.

Acknowledgments

LZ and GK are supported by the Ligue contre le Cancer (équipes labellisées, Program “Equipe labelisée LIGUE”; no. EL2016.LNCC (VT/PLP)); Agence National 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; Chancellerie 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). MF is supported by the Seerave Foundation and the European Union’s Horizon Europe research and innovation program under grant agreement number 101095604 - GAP-101095604 -[project acronym: PREVALUNG-EU, project title: Personalized lung cancer risk assessment leading to stratified Interception].

Disclosure of potential conflicts of interest

LZ has held research contracts with Glaxo Smyth Kline, Incyte, Lytix, Kaleido, Innovate Pharma, Daiichi Sankyo, Pilege, Merus, Transgene, 9 m, Tusk and Roche, was on the on the Board of Directors of Transgene, is a cofounder of EverImmune, and holds patents covering the treatment of cancer and the therapeutic manipulation of the microbiota. 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 with 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 Association pour la Recherche sur le Cancer Cancéropôle Ile de France European Research Area Network on Cardiovascular Diseases [ERA-CVD, MINOTAUR]; Fondation Leducq Fondation pour la Recherche Médicale Institut National Du Cancer Institut National de la Santé et de la Recherche Médicale Institut Universitaire de France Ligue Contre le Cancer [EL2016.LNCC (VT/PLP)]; the RHU Torino Lumière the LabEx Immuno-Oncology [ANR-18-IDEX-0001]; Fondation Carrefour the European Union Horizon 2020 Project Oncobiome Gustave Roussy Odyssea a donation by Elior Chancellerie des universités de Paris (Legs Poix) Association “Le Cancer du Sein, Parlons-en!” AMMICa US23/CNRS UMS3655 the SIRIC Cancer Research and Personalized Medicine (CARPEM) the RHU Torino Lumière; the Seerave Foundation the European Union’s Horizon Europe research and innovation program [PREVALUNG-EU 101095604]; the SIRIC Stratified Oncology Cell DNA Repair and Tumor Immune Elimination (SOCRATE) Seerave Foundation