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 5

Epigenetic reprogramming of mPTCLs into NK-like cells.

Options: View larger image (or click on image) Download as PowerPoint
Epigenetic reprogramming of mPTCLs into NK-like cells. (A) Unsupervised ...
(A) Unsupervised clustering (Euclidean distance, Ward agglomeration method) of mPTCL cells, immature and mature T cell populations, as well as mature NK cells from ImmGen and from our own cohort, based on the normalized accessibility of all 98,375 OCRs identified in ATAC-Seq. (B) Each bar represents a gene expression–based signature of a specific mouse cell population in the ImmGen atlas, colored according to broader population classes. Bar lengths (x axis) indicate the statistical significance of the overlap between genes in the signature and genes with differential chromatin accessibility in ATAC-Seq between mPTCL cells and normal T cells (ToppFun coexpression test FDR < 0.01). Cell populations whose representative genes harbor OCRs more accessible in normal T cells and mPTCL cells are presented respectively in the left and right panels. (C) Heatmap of chromatin accessibility in the 51 OCRs located in the promoter regions of genes involved in NK signatures presented in Figure 4E. (D) ATAC-Seq tracks from normal T cells, NKT cells, and NK cells, as well as mPTCL cells around Tyrobp and Ncr1 (average TMM-normalized CPMs per group in 50 bp wide bins). OCRs surrounded in red are significantly different (FDR < 5%) between conditions (mPTCL ≠ T and NKT; NK ≠ T and NKT).