4.8 Article

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

Journal

JOURNAL OF CLINICAL INVESTIGATION
Volume 131, Issue 13, Pages -

Publisher

AMER SOC CLINICAL INVESTIGATION INC
DOI: 10.1172/JCI139675

Keywords

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Funding

  1. French National Research Council (Agence Nationale de la Recherche [ANR])
  2. Centers for Biological Resources of Lyon (BRIF) [BB-0033-00046, BB-0033-00069]
  3. European Union Transcan2 ERANETPLL grant
  4. INSERM, The Institut Carnot CALYM, La Ligue Nationale Contre le Cancer (LNCC) - Equipe Labellisee LIGUE [INCaDGOSINSERM_12563]
  5. Fondation pour la Recherche Medicale (FRM) fellowship

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Chronic TCR stimulation may drive T cell lymphomagenesis, but does not affect PTCL cell survival. NK cell-like reprogramming may occur in PTCL cells, with expression of NK receptors and downstream signaling molecules.
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.

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