Journal Article

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

Verney, Aurélie, Fezelot, Caroline, Bachy, Emmanuel, de Leval, Laurence, Lours, Camille, Iqbal, Javeed, Walzer, Thierry, Salles, Gilles, Ferrari, Anthony, Carras, Sylvain, Bouska, Alyssa, Lefebvre, Christine, Mareschal, Sylvain, Julia, Edith, Gaulard, Philippe, Sujobert, Pierre, Rouault, Jean-Pierre, Blery, Mathieu, Traverse-Glehen, Alexandra, Marçais, Antoine, Urb, Mirjam, Courtois, Lucien, Heiblig, Maël, Robinot, Rémy, Chebel, Amel, Genestier, Laurent, Sharma, Sunandini, Pommier, Roxane M., Bardel, Emilie, Chartoire, Dimitri, Bertheau, Charlotte, Sibon, David

2021

Overview

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.

• Publisher: American Society for Clinical Investigation
• Subject: Addictions / Animals / Antigen receptors, T cell / Biomedical research / Cancer / Carcinogenesis - genetics / Carcinogenesis - immunology / Celiac disease / Cell survival / Cellular Reprogramming - genetics / Cellular Reprogramming - immunology / Cellular signal transduction / Cytokines / Development and progression / Epigenesis, Genetic / Epigenetic inheritance / Epigenetics / Gene expression / Gene Expression Regulation, Neoplastic / Genes, p53 / Genetic aspects / Health aspects / Humans / Killer cells / Killer Cells, Natural - immunology / Kinases / Leukemia / Life Sciences / Lymphocyte transformation / Lymphocytes / Lymphocytes T / Lymphoma / Lymphoma, T-Cell, Peripheral - genetics / Lymphoma, T-Cell, Peripheral - immunology / Lymphoma, T-Cell, Peripheral - metabolism / Medical prognosis / Mice / Mice, Inbred C57BL / Mice, Knockout / Mutation / Natural killer cells / Neoplasms, Experimental - genetics / Neoplasms, Experimental - immunology / Neoplasms, Experimental - metabolism / Non-Hodgkin's lymphomas / Oncology, Experimental / Phenotypes / Receptors / Receptors, Antigen, T-Cell - genetics / Receptors, Antigen, T-Cell - immunology / Receptors, Natural Killer Cell - genetics / Receptors, Natural Killer Cell - immunology / Signal Transduction - genetics / Signal Transduction - immunology / Syk Kinase - metabolism / Syk protein / T cell receptors / T cells / T-cell lymphoma / T-Lymphocytes - immunology / TOR protein / Transcriptomes