Peripheral T-cell lymphomas (PTCLs) represent a significant unmet medical need with dismal clinical outcome. T-cell receptor (TCR) is emerging as a key driver of T lymphocytes transformation. However, the role of chronic TCR activation in lymphomagenesis and in survival of lymphoma cells is still poorly understood. Using an original mouse model, we report here that chronic TCR stimulation drives T-cell lymphomagenesis whereas TCR signaling does not contribute to PTCL survival. The combination of kinome, transcriptome and epigenome analyses of mouse PTCLs revealed a NK-like reprogramming of PTCL cells with expression of NK receptors (NKRs) and downstream signaling molecules such as Tyrobp and Syk. Activating NKR were functional in PTCLs and dependent of Syk activity. In vivo blockade of NKR signaling prolonged mouse survival, demonstrating the addiction of PTCLs to NKR and downstream Syk/mTOR activity for their survival. Studying a large collection of human primary samples, we identified several PTCLs recapitulating the phenotype described in this model by expressing NKR and Syk, suggesting similar mechanism of lymphomagenesis and establishing rationales for clinical trials targeting such molecules.
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 Bléry, Gilles Salles, Thierry Walzer, Emmanuel Bachy, Laurent Genestier