Chronic T cell receptor stimulation unmasks NK receptor signaling in peripheral T cell lymphomas via epigenetic reprogramming
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
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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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 8

mPTCL cells rely on NKaR signaling for survival.

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mPTCL cells rely on NKaR signaling for survival. (A) Kaplan-Meier surviv...
(A) Kaplan-Meier survival curves for WT mice (n = 5 for each group) transferred with mPTCL cells genetically invalidated for Klrk1 (sgNKG2D), Ncr1 (sgNKp46), or both, using Alt-R CRISPR/Cas9 sgRNA targeting these genes, or transfected with control sgRNA. **P < 0.01, by log-rank test with Holm’s post hoc correction. Data are representative of 2 independent experiments using different mPTCL cells. (B) Kaplan-Meier survival curves for mPTCL-bearing NSG mice treated with isotype control or anti-NKp46– and anti-NKG2D–blocking mAbs alone or in combination (n = 6 for each group). **P < 0.01, by log-rank test with Holm’s post hoc correction. Data are representative of 3 independent experiments using different PTCLs. (C) Representative 3D reconstruction of spleen and liver of mPTCL-bearing NSG mice treated with isotype control or a combination of anti-NKp46– and anti-NKG2D–blocking mAbs and sacrificed 12 days after PTCL transfer for analysis. (D) Spleen and liver volumes of mPTCL-bearing NSG mice treated with a combination of anti-NKp46– and anti-NKG2D–blocking mAbs or isotype control 12 days after PTCL transfer (isotype control group, n = 5; mAb-treated group, n = 5). P values were determined by Mann-Whitney U test. (E) FACS analysis of p-SYK, p-PLCγ2, p-AKT, and p-S6 and associated scatter plots of mPTCL cells from PTCL-bearing mice treated with anti-NKG2D– and anti-NKp46–blocking mAbs (n = 4) or isotype control (n = 4). (F) Kaplan-Meier survival curves for WT mice (n = 5 for each group) transferred with mPTCL cells genetically invalidated for Syk (sgSYK) or transfected with control sgRNA. P value was determined by log-rank test. Data are representative of 2 independent experiments using different mPTCLs. (G) Kaplan-Meier survival curves for mPTCL-bearing NSG mice treated with vehicle alone (Ctrl) or with either P505-15 (20 mg/kg) or cerdulatinib (20 mg/kg). *P < 0.05 and **P < 0.01, by log-rank test with Holm’s post hoc correction. Data are representative of 2 independent experiments using different PTCLs. (H) Kaplan-Meier survival curves for mPTCL-bearing NSG mice treated with vehicle control or rapamycin. P value was determined by log-rank test. Data are representative of 2 independent experiments using different PTCLs.