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

Author

Listed:
  • 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
    Université de Paris
    Service de Biothérapie et Thérapie Génique Clinique, Assistance Publique–Hôpitaux de Paris, Hôpital Necker)

  • 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
    INSERM U976)

  • Dany Anglicheau

    (Université de Paris
    Service de Transplantation rénale adulte, Assistance Publique-Hôpitaux de Paris, Hôpital Necker
    INSERM U1151, Institut Necker Enfants Malades)

  • Christophe Legendre

    (Université de Paris
    Service de Transplantation rénale adulte, Assistance Publique-Hôpitaux de Paris, Hôpital Necker)

  • Jean-Luc Taupin

    (Université de Paris
    Laboratoire d’immunologie et histocompatibilité, Assistance Publique-Hôpitaux de Paris, Hôpital Saint-Louis)

  • 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
    Université de Paris
    Service de Biothérapie et Thérapie Génique Clinique, Assistance Publique–Hôpitaux de Paris, Hôpital Necker)

  • Isabelle André

    (Laboratoire de lymphohématopoïèse humaine, INSERM UMR 1163, IHU IMAGINE)

  • Julien Zuber

    (Laboratoire de lymphohématopoïèse humaine, INSERM UMR 1163, IHU IMAGINE
    Université de Paris
    Service de Transplantation rénale adulte, Assistance Publique-Hôpitaux de Paris, Hôpital Necker)

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.

Suggested Citation

  • Baptiste Lamarthée & Armance Marchal & Soëli Charbonnier & Tifanie Blein & Juliette Leon & Emmanuel Martin & Lucas Rabaux & Katrin Vogt & Matthias Titeux & Marianne Delville & Hélène Vinçon & Emmanuel, 2021. "Transient mTOR inhibition rescues 4-1BB CAR-Tregs from tonic signal-induced dysfunction," Nature Communications, Nature, vol. 12(1), pages 1-19, December.
    • Handle: RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-26844-1
    DOI: 10.1038/s41467-021-26844-1
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    References listed on IDEAS

    as
    1. Norihiko Watanabe & Yi-Hong Wang & Heung Kyu Lee & Tomoki Ito & Yui-Hsi Wang & Wei Cao & Yong-Jun Liu, 2005. "Hassall's corpuscles instruct dendritic cells to induce CD4+CD25+ regulatory T cells in human thymus," Nature, Nature, vol. 436(7054), pages 1181-1185, August.
    2. Tao Xu & Kelly M. Stewart & Xiaohu Wang & Kai Liu & Min Xie & Jae Kyu Ryu & Ke Li & Tianhua Ma & Haixia Wang & Lu Ni & Saiyong Zhu & Nan Cao & Dongwei Zhu & Yu Zhang & Katerina Akassoglou & Chen Dong , 2017. "Metabolic control of TH17 and induced Treg cell balance by an epigenetic mechanism," Nature, Nature, vol. 548(7666), pages 228-233, August.
    3. Hu Zeng & Kai Yang & Caryn Cloer & Geoffrey Neale & Peter Vogel & Hongbo Chi, 2013. "mTORC1 couples immune signals and metabolic programming to establish Treg-cell function," Nature, Nature, vol. 499(7459), pages 485-490, July.
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