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 4

Murine PTCLs downregulate T cell genes and express a NK-like transcriptome.

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Murine PTCLs downregulate T cell genes and express a NK-like transcripto...
(A) Volcano plot of genes differentially expressed between mPTCL cells (n = 9) and normal T cells (n = 6). The vertical black lines delimit the 2-FC effects. Upregulated genes in mPTCL cells compared with normal T cells are located on the right and downregulated genes on the left. Informative upregulated genes have been color-coded in red and the downregulated in blue. (B) Unsupervised clustering (using the Euclidean distance, Ward agglomeration method) based on the 1% of genes most variably expressed between immature and mature T cell populations as well as mature NK cells (data are from ImmGen and our own cohort). This clustering analysis generated 3 gene clusters (1, 2, and 3), defined on the left of the panel. (C) Representation of the 5 most highly significant C2 (Molecular Signatures Database [MSigDB]) gene set names of the 3 different gene clusters defined in B. (D) Comparison of genes differentially expressed between normal NK and T cells (y axis) and mPTCLs and normal T cells (x axis). Yellow dots correspond to genes differentially expressed, at a multiple-testing, adjusted P value of 0.05, between NK and T cells; blue dots correspond to genes differentially expressed between mPTCLs and T cells; and green dots represent genes differentially expressed in both conditions. The names of some of the most informative genes are indicated in the upper-right and lower-left quadrants.