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

Autor: Lamarthée B; Laboratoire de lymphohématopoïèse humaine, INSERM UMR 1163, IHU IMAGINE, Paris, France., Marchal A; Laboratoire de lymphohématopoïèse humaine, INSERM UMR 1163, IHU IMAGINE, Paris, France., Charbonnier S; Laboratoire de lymphohématopoïèse humaine, INSERM UMR 1163, IHU IMAGINE, Paris, France., Blein T; Laboratoire de lymphohématopoïèse humaine, INSERM UMR 1163, IHU IMAGINE, Paris, France., Leon J; Department of Immunology, Harvard Medical School, Boston, MA, 02115, USA., Martin E; Lymphocyte activation and susceptibility to EBV, INSERM UMR 1163, IHU IMAGINE, Paris, France., Rabaux L; Laboratoire de lymphohématopoïèse humaine, INSERM UMR 1163, IHU IMAGINE, Paris, France., Vogt K; Department of Immunology, Charité University Hospital, Berlin, Germany., Titeux M; Maladie génétique cutanée, INSERM UMR 1163, IHU IMAGINE, Paris, France., Delville M; Laboratoire de lymphohématopoïèse humaine, INSERM UMR 1163, IHU IMAGINE, Paris, France.; Université de Paris, Paris, France.; Service de Biothérapie et Thérapie Génique Clinique, Assistance Publique-Hôpitaux de Paris, Hôpital Necker, Paris, France., Vinçon H; Laboratoire de lymphohématopoïèse humaine, INSERM UMR 1163, IHU IMAGINE, Paris, France., Six E; Laboratoire de lymphohématopoïèse humaine, INSERM UMR 1163, IHU IMAGINE, Paris, France., Pallet N; Université de Paris, INSERM U1138, Centre de Recherche des Cordeliers, 75006, Paris, France., Michonneau D; Université de Paris, Paris, France.; INSERM U976, Paris, France., Anglicheau D; Université de Paris, Paris, France.; Service de Transplantation rénale adulte, Assistance Publique-Hôpitaux de Paris, Hôpital Necker, Paris, France.; INSERM U1151, Institut Necker Enfants Malades, Paris, France., Legendre C; Université de Paris, Paris, France.; Service de Transplantation rénale adulte, Assistance Publique-Hôpitaux de Paris, Hôpital Necker, Paris, France., Taupin JL; Université de Paris, Paris, France.; Laboratoire d'immunologie et histocompatibilité, Assistance Publique-Hôpitaux de Paris, Hôpital Saint-Louis, Paris, France., Nemazanyy I; Plateforme de Métabolique, Structure Fédérative de Recherche, Necker, INSERM US24/CNRS UMS, 3633, Paris, France., Sawitzki B; Department of Immunology, Charité University Hospital, Berlin, Germany., Latour S; Lymphocyte activation and susceptibility to EBV, INSERM UMR 1163, IHU IMAGINE, Paris, France., Cavazzana M; Laboratoire de lymphohématopoïèse humaine, INSERM UMR 1163, IHU IMAGINE, Paris, France.; Université de Paris, Paris, France.; Service de Biothérapie et Thérapie Génique Clinique, Assistance Publique-Hôpitaux de Paris, Hôpital Necker, Paris, France., André I; Laboratoire de lymphohématopoïèse humaine, INSERM UMR 1163, IHU IMAGINE, Paris, France., Zuber J; Laboratoire de lymphohématopoïèse humaine, INSERM UMR 1163, IHU IMAGINE, Paris, France. julien.zuber@aphp.fr.; Université de Paris, Paris, France. julien.zuber@aphp.fr.; Service de Transplantation rénale adulte, Assistance Publique-Hôpitaux de Paris, Hôpital Necker, Paris, France. julien.zuber@aphp.fr.
Jazyk: angličtina
Zdroj: Nature communications [Nat Commun] 2021 Nov 08; Vol. 12 (1), pp. 6446. Date of Electronic Publication: 2021 Nov 08.
DOI: 10.1038/s41467-021-26844-1
Abstrakt: 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.
(© 2021. The Author(s).)
Databáze: MEDLINE
Externí odkaz: