T-cell lymphoma
Peripheral T-cell lymphomas (PTCL) represent 10% of non-Hodgkin lymphomas. They are characterized by their great heterogeneity (more than 30 entities), their aggressiveness and their poor prognosis (30% survival at 5 years), highlighting the need for innovative therapeutic approaches. T-cell receptor (TCR) signaling is the major growth-regulatory machinery of normal T cells.
We therefore hypothesized that it may also retain an integral role in mature T-cell tumorigenesis. Knowing that TP53 is one of the most recurrent altered gene in human PTCL, we recently developed 2 new mouse models of PTCL using p53-/- mice, in which we demonstrated the pivotal role of TCR signaling in lymphomagenesis (Bachy et al. J Exp Med 2016 and Robinot et al. Blood 2018). To better understand the mechanisms of NKT lymphomagenesis, we performed whole exome sequencing of 6 NKTL and identified a recurrent deletion of an epigenetic regulator gene involved in NKT-cell differentiation.
We will therefore study:
- its role in NKT lymphomagenesis,
- its targets in NKT cells using ATAC-seq and CHIP-seq,
- its alterations in human PTCL,
- potential therapeutic target.
The role of chronic TCR stimulation in conventional T-cell lymphomagenesis has also been investigated thanks to a second mouse model in which p53-deficient T cells have been subjected to homeostatic proliferation, known to be driven by chronic TCR stimulation and cytokine (Figure 1). In this model, 60 % of recipient mice developed a PTCL that has been reprogrammed to NK-like cells expressing NK receptor (NKR), NKR signaling kinases and cytotoxic molecules. This NK-like reprogramming promotes PTCL addiction to NK receptor signaling through Syk and mTORC1 for survival in vivo (Carras et al. J Clin Invest 2021).
Using a cohort of 60 human primary PTCL samples, we identified in collaboration with T. Walzer (CIRI) several PTCL expressing NKR and Syk, suggesting the role of chronic TCR stimulation in their lymphomagenesis. Among NKR, KIR3DL2 was expressed in 42% of PTCL analyzed, reinforcing the interest for enlarging the use of the anti-KIR3DL2 immunotherapy (Lacutamab) in PTCL. Thanks to a partnership between Innate Pharma and LYSA (www.lysa-lymphoma.org) a new multi-cohort phase 2 trial (KILT) is currently considered to assess the impact of lacutamab in combination with GEMOX in such PTCLs at relapse.
These projects are funded the Institut Carnot CALYM, the Ligue Nationale Contre le Cancer (LNCC) Equipe Labellisée LIGUE 2017, INCa-DGOS-INSERM_12563 for the LYriCAN project, the Fondation pour la Recherche Médicale (FRM), and by the European Union Transcan-2 “ERANET-PLL” grant.
Figure 1: Impact of chronic TCR simulation on NK-like reprogramming and T-cell lymphomagenesis.