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.
View: Text | PDF
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

×

Figure 3

SYK and downstream signaling pathways are constitutively activated in mPTCLs.

Options: View larger image (or click on image) Download as PowerPoint
SYK and downstream signaling pathways are constitutively activated in mP...
(A) Volcano plot representation of the PamGene GeneGO analysis of tyrosine kinase activation in mPTCL cells (n = 18) compared with normal T cells (n = 3). The peptide contribution to upstream kinases was determined. (B) Western blots show the expression of SYK and ZAP70, as well as the expression and activation of PLCγ1, PLCγ2, AKT, and ERK in mPTCL cells compared with purified and stimulated (stim) normal B and T cells from WT mice, used as positive control. GAPDH was used as a loading control. (C) Representative FACS analysis of SYK tyrosine phosphorylation (pY342-SYK ) in mPTCL cells (red) in the basal state (red solid line) and after SYK pharmacological inhibition with P505-15 (red dashed line), as well as in control B cells (blue) in the basal state (blue dashed line) and after B cell receptor (BCR) stimulation (blue solid line), as measured by flow cytometry. Associated scatter plot shows SYK tyrosine phosphorylation expressed as the ΔMFI between basal and P505-15–treated mPTCL cells (n = 8) compared with the ΔMFI between basal and BCR-stimulated B cells (n = 3), or between basal and TCR-stimulated T cells (n = 3). (D) Representative FACS analysis of pS235–236-S6 in mPTCL cells (red) or control T cells (gray) in the basal state (solid lines), as well as after mTORC1 pharmacological inhibition with rapamycin (dash lines). Associated scatter plot shows the ΔMFI between basal and rapamycin-treated conditions in mPTCL cells (n = 6) compared with T cells (n = 3). (E) Immunohistochemical staining for CD3, SYK, and PLCγ2 in representative mPTCL cells (liver). Scale bars: 100 μm. (F) Immunohistochemical staining for CD30, SYK, and PLCγ2 in representative human ALK+ ALCL. (G) SYK and PLCγ2 expression in lymphoma cells from 7 different entities of human PTCLs. The TFH-PTCLs include AITL and PTCL-NOS with TFH-like features according to the 2016 WHO classification.