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Chronic T cell receptor stimulation unmasks NK receptor signaling in peripheral T cell lymphomas via epigenetic reprogramming

Sylvain Carras 1, 2, 3 Dimitri Chartoire 1, 2, 3 Sylvain Mareschal 1, 2, 3 Maël Heiblig 1, 2, 3 Antoine Marçais 4 Rémy Robinot 1, 2, 3 Mirjam Urb 1, 2, 3 Roxane Pommier 5 Edith Julia 1, 2, 3 Amel Chebel 1, 2, 3 Aurélie Verney 1, 2, 3 Charlotte Bertheau 2 Emilie Bardel 1, 2, 3 Caroline Fezelot 1, 2, 3 Lucien Courtois 1, 2, 3 Camille Lours 1, 2, 3 Alyssa Bouska 6 Sunandini Sharma 6 Christine Lefebvre 7, 8 Jean-Pierre Rouault 1, 2, 3 David Sibon 9 Anthony Ferrari 5 Javeed Iqbal 6 Laurence de Leval 10 Philippe Gaulard 11, 12 Alexandra Traverse-Glehen 1, 2, 3 Pierre Sujobert 1, 2, 3, 13 Mathieu Blery 14 Gilles Salles 1, 2, 3 Thierry Walzer 4 Emmanuel Bachy 1, 2, 3 Laurent Genestier 1, 2, 3
Abstract : Peripheral T cell lymphomas (PTCLs) represent a significant unmet medical need with dismal clinical outcomes. The T cell receptor (TCR) is emerging as a key driver of T lymphocyte transformation. However, the role of chronic TCR activation in lymphomagenesis and in lymphoma cell survival is still poorly understood. Using a mouse model, we report that chronic TCR stimulation drove T cell lymphomagenesis, whereas TCR signaling did not contribute to PTCL survival. The combination of kinome, transcriptome, and epigenome analyses of mouse PTCLs revealed a NK cell-like reprogramming of PTCL cells with expression of NK receptors (NKRs) and downstream signaling molecules such as Tyrobp and SYK. Activating NKRs were functional in PTCLs and dependent on SYK activity. In vivo blockade of NKR signaling prolonged mouse survival, demonstrating the addiction of PTCLs to NKRs and downstream SYK/mTOR activity for their survival. We studied a large collection of human primary samples and identified several PTCLs recapitulating the phenotype described in this model by their expression of SYK and the NKR, suggesting a similar mechanism of lymphomagenesis and establishing a rationale for clinical studies targeting such molecules.
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https://www.hal.inserm.fr/inserm-03280949
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Submitted on : Wednesday, July 7, 2021 - 5:27:26 PM
Last modification on : Wednesday, July 21, 2021 - 4:10:02 PM

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Sylvain Carras, Dimitri Chartoire, Sylvain Mareschal, Maël Heiblig, Antoine Marçais, et al.. Chronic T cell receptor stimulation unmasks NK receptor signaling in peripheral T cell lymphomas via epigenetic reprogramming. The Journal of clinical investigation, 2021, 131 (13), pp.e139675. ⟨10.1172/jci139675⟩. ⟨inserm-03280949⟩

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