Transient mTOR inhibition rescues 4-1BB CAR-Tregs from tonic signal-induced dysfunction

Baptiste Lamarthée, Armance Marchal, Soëli Charbonnier, Tifanie Blein, Juliette Leon, Emmanuel Martin, Lucas Rabaux, Katrin Vogt, Matthias Titeux, Marianne Delville, Hélène Vinçon, Emmanuelle Six, Nicolas Pallet, David Michonneau, Dany Anglicheau, Christophe Legendre, Jean-Luc Taupin, Ivan Nemazanyy, Birgit Sawitzki, Sylvain Latour, Marina Cavazzana, Isabelle André and Julien Zuber ()
Additional contact information
Baptiste Lamarthée: Laboratoire de lymphohématopoïèse humaine, INSERM UMR 1163, IHU IMAGINE
Armance Marchal: Laboratoire de lymphohématopoïèse humaine, INSERM UMR 1163, IHU IMAGINE
Soëli Charbonnier: Laboratoire de lymphohématopoïèse humaine, INSERM UMR 1163, IHU IMAGINE
Tifanie Blein: Laboratoire de lymphohématopoïèse humaine, INSERM UMR 1163, IHU IMAGINE
Juliette Leon: Harvard Medical School
Emmanuel Martin: Lymphocyte activation and susceptibility to EBV, INSERM UMR 1163, IHU IMAGINE
Lucas Rabaux: Laboratoire de lymphohématopoïèse humaine, INSERM UMR 1163, IHU IMAGINE
Katrin Vogt: Charité University Hospital
Matthias Titeux: Maladie génétique cutanée, INSERM UMR 1163, IHU IMAGINE
Marianne Delville: Laboratoire de lymphohématopoïèse humaine, INSERM UMR 1163, IHU IMAGINE
Hélène Vinçon: Laboratoire de lymphohématopoïèse humaine, INSERM UMR 1163, IHU IMAGINE
Emmanuelle Six: Laboratoire de lymphohématopoïèse humaine, INSERM UMR 1163, IHU IMAGINE
Nicolas Pallet: Université de Paris, INSERM U1138, Centre de Recherche des Cordeliers
David Michonneau: Université de Paris
Dany Anglicheau: Université de Paris
Christophe Legendre: Université de Paris
Jean-Luc Taupin: Université de Paris
Ivan Nemazanyy: Plateforme de Métabolique, Structure Fédérative de Recherche, Necker, INSERM US24/CNRS UMS
Birgit Sawitzki: Charité University Hospital
Sylvain Latour: Lymphocyte activation and susceptibility to EBV, INSERM UMR 1163, IHU IMAGINE
Marina Cavazzana: Laboratoire de lymphohématopoïèse humaine, INSERM UMR 1163, IHU IMAGINE
Isabelle André: Laboratoire de lymphohématopoïèse humaine, INSERM UMR 1163, IHU IMAGINE
Julien Zuber: Laboratoire de lymphohématopoïèse humaine, INSERM UMR 1163, IHU IMAGINE

Nature Communications, 2021, vol. 12, issue 1, 1-19

Abstract: Abstract The use of chimeric antigen receptor (CAR)-engineered regulatory T cells (Tregs) has emerged as a promising strategy to promote immune tolerance. However, in conventional T cells (Tconvs), CAR expression is often associated with tonic signaling, which can induce CAR-T cell dysfunction. The extent and effects of CAR tonic signaling vary greatly according to the expression intensity and intrinsic properties of the CAR. Here, we show that the 4-1BB CSD-associated tonic signal yields a more dramatic effect in CAR-Tregs than in CAR-Tconvs with respect to activation and proliferation. Compared to CD28 CAR-Tregs, 4-1BB CAR-Tregs exhibit decreased lineage stability and reduced in vivo suppressive capacities. Transient exposure of 4-1BB CAR-Tregs to a Treg stabilizing cocktail, including an mTOR inhibitor and vitamin C, during ex vivo expansion sharply improves their in vivo function and expansion after adoptive transfer. This study demonstrates that the negative effects of 4-1BB tonic signaling in Tregs can be mitigated by transient mTOR inhibition.

Date: 2021
References: View references in EconPapers View complete reference list from CitEc
Citations:

Downloads: (external link)
https://www.nature.com/articles/s41467-021-26844-1 Abstract (text/html)

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-26844-1

Ordering information: This journal article can be ordered from
https://www.nature.com/ncomms/

DOI: 10.1038/s41467-021-26844-1

Access Statistics for this article

Nature Communications is currently edited by Nathalie Le Bot, Enda Bergin and Fiona Gillespie

More articles in Nature Communications from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().