Journal Article

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

Leon, Juliette, Michonneau, David, Vinçon, Hélène, Anglicheau, Dany, Nemazanyy, Ivan, Taupin, Jean-Luc, Sawitzki, Birgit, Latour, Sylvain, Rabaux, Lucas, Cavazzana, Marina, Martin, Emmanuel, Charbonnier, Soëli, Legendre, Christophe, André, Isabelle, Blein, Tifanie, Delville, Marianne, Pallet, Nicolas, Vogt, Katrin, Lamarthée, Baptiste, Six, Emmanuelle, Zuber, Julien, Marchal, Armance, Titeux, Matthias

2021

Overview

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. Chimeric antigen receptor engineering in T cells has been shown to be of great potential therapeutic benefit in a range of immune pathologies, although the functionality of such cell therapies can be limited due to tonic signalling and the induction of dysfunction. Here the authors show transient inhibition of mTOR can rescue their 41-BB-CAR-Tregs from tonic signalling-induced dysfunction.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 14/1 / 38/91 / 42 / 59/5 / 631/250/1854/2812 / 631/250/2520 / 631/250/516 / 64/60 / Adoptive transfer / Animals / Antigens / Ascorbic acid / CD28 antigen / CD28 Antigens - immunology / CD28 Antigens - metabolism / Chimeric antigen receptors / Graft vs Host Disease - immunology / Graft vs Host Disease - therapy / HLA-A2 Antigen - immunology / HLA-A2 Antigen - metabolism / Humanities and Social Sciences / Humans / Immunological tolerance / Immunoregulation / Immunosuppressive Agents - pharmacology / Immunotherapy, Adoptive - methods / In vivo methods and tests / Jurkat Cells / Life Sciences / Lymphocytes / Lymphocytes T / Male / Mice / Mice, Inbred NOD / Mice, Knockout / Mice, SCID / multidisciplinary / Receptors / Receptors, Chimeric Antigen - immunology / Receptors, Chimeric Antigen - metabolism / Science / Science (multidisciplinary) / Signal Transduction - drug effects / Signal Transduction - immunology / Signaling / Sirolimus - pharmacology / T-Lymphocytes, Regulatory - cytology / T-Lymphocytes, Regulatory - immunology / T-Lymphocytes, Regulatory - metabolism / TOR protein / TOR Serine-Threonine Kinases - antagonists & inhibitors / TOR Serine-Threonine Kinases - immunology / TOR Serine-Threonine Kinases - metabolism / Transplantation, Heterologous / Tumor Necrosis Factor Receptor Superfamily, Member 9 - immunology / Tumor Necrosis Factor Receptor Superfamily, Member 9 - metabolism