Chronic T cell receptor stimulation unmasks NK receptor signaling in peripheral T cell lymphomas via epigenetic reprogramming
Sylvain Carras, … , Emmanuel Bachy, Laurent Genestier
Sylvain Carras, … , Emmanuel Bachy, Laurent Genestier
Published May 27, 2021
Citation Information: J Clin Invest. 2021;131(13):e139675. https://doi.org/10.1172/JCI139675.
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Research Article Hematology Immunology

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

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.

Authors

Sylvain Carras, Dimitri Chartoire, Sylvain Mareschal, Maël Heiblig, Antoine Marçais, Rémy Robinot, Mirjam Urb, Roxane M. Pommier, Edith Julia, Amel Chebel, Aurélie Verney, Charlotte Bertheau, Emilie Bardel, Caroline Fezelot, Lucien Courtois, Camille Lours, Alyssa Bouska, Sunandini Sharma, Christine Lefebvre, Jean-Pierre Rouault, David Sibon, Anthony Ferrari, Javeed Iqbal, Laurence de Leval, Philippe Gaulard, Alexandra Traverse-Glehen, Pierre Sujobert, Mathieu Blery, Gilles Salles, Thierry Walzer, Emmanuel Bachy, Laurent Genestier

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Figure 1

Chronic TCR stimulation promotes T cell lymphomagenesis.

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Chronic TCR stimulation promotes T cell lymphomagenesis. (A) Kaplan-Meie...
(A) Kaplan-Meier survival curves for CD3ε–/– mice receiving WT cells (WT>CD3εKO, squares, n = 20) or p53–/– T cells (p53KO>CD3εKO, circles, n = 80) and for WT (C57BL6 CD451.1) mice receiving p53–/– T cells (CD451.2) (p53KO>WT, triangle, n = 11). In the WT>CD3εKO group, recipient mice alive on day 450 were sacrificed and evaluated. For the p53KO>WT group, all mice were still alive 450 days after transfer. ****P < 0.0001, by log-rank test and Holm’s post hoc correction. For the p53KO>CD3εKO group, the circles are colored according to the mouse’s cause of death: data points for mice that died of PTCL are shown in red, thymic lymphomas (TL) in black, and others (no lymphoma) in white. (B) Spectrum of causes of death for p53KO>CD3εKO or WT>CD3εKO mice. Mice alive on day 450 were categorized as “alive” and were then sacrificed. (C) Representative histological micrographs of formalin-fixed, H&E- or anti-CD3–stained liver, spleen, and LNs obtained from a mPTCL. Scale bars: 100 μm; 400 μm. (D) Pie chart representation of TCRVβ clonality in 3 representative mPTCL samples among 16 tested. (E) Surface expression of CD62L, CD44, CD122, CD54, and B220 measured by flow cytometry (ΔMFI) in mPTCL cells (n = 26) compared with normal T cells (n = 3). P values were determined by Mann-Whitney U test comparing mPTCL cells with control T cells.