Page 137 - Haematologica Vol. 110 - January 2025

ARTICLE - Non-Hodgkin Lymphoma
Deep phenotyping of nodal T-cell lymphomas reveals
immune alterations and therapeutic targets
Pierre Stephan,1 Jimmy Perrot,2 Allison Voisin,1 Maud Barbery,1 Thibault Andrieu,1 Maxime Grimont,1 Julie Caramel,1 Mathilde Bardou,2 Garance Tondeur,2 Edoardo Missiaglia,3 Philippe Gaulard,4 François Lemmonier,4 Laurence de Leval,3 Emmanuel Bachy,2,5 Pierre Sujobert,2,5 Laurent Genestier,5 Alexandra Traverse-Glehen2 and Yenkel Grinberg-Bleyer1
1Cancer Research Center of Lyon, UMR INSERM 1052, CNRS 5286, Université Claude Bernard Lyon 1, Labex DEV2CAN, Centre Léon Bérard, Lyon, France; 2Centre Hospitalier Lyon Sud and Université Claude Bernard Lyon-1, Pierre-Bénite, France; 3Institute of Pathology, Department of Laboratory Medicine and Pathology, Lausanne University Hospital and Lausanne University, Lausanne, Switzerland; 4AP-HP, Henri Mondor Hospital, Pathology Department, Créteil, France, and University Paris Est Créteil, INSERM, IMRB, Créteil, France and 5Centre International de Recherche en Infectiologie (CIRI), Team Lymphoma Immuno-Biology, UMR INSERM U1111, CNRS 5308, Université Claude Bernard Lyon I, ENS de Lyon, Lyon, France
Abstract
Whereas immunotherapies have revolutionized the treatment of different solid and hematologic cancers, their efficacy in nodal peripheral T-cell lymphomas (PTCL) is limited, due to a lack of understanding of the immune response they trigger. To fully characterize the immune tumor microenvironment (TME) of PTCL, we performed spectral flow cytometry analyses on 11 angioimmunoblastic T-cell lymphomas (AITL), 7 PTCL, not otherwise specified (PTCL, NOS) lymph node samples, and 10 non-tu- moral control samples. The PTCL TME contained a larger proportion of regulatory T cells and exhausted CD8+ T cells, with enriched expression of druggable immune checkpoints. Interestingly, CD39 expression was up-regulated at the surface of most immune cells, and a multi-immunofluorescence analysis on a retrospective cohort of 43 AITL patients demonstrated a signif- icant association between high CD39 expression by T cells and poor patient prognosis. Together, our study unravels the com- plex TME of nodal PTCL, identifies targetable immune checkpoints, and highlights CD39 as a novel prognostic factor.
Introduction
Peripheral T-cell lymphomas (PTCL) are highly hetero- geneous neoplasms derived from post-thymic T cells or mature natural killer (NK) cells, and represent 10-15% of non-Hodgkin lymphomas.1 The two most common sub- types in Western countries are angioimmunoblastic T-cell lymphomas (AITL) and peripheral T-cell lymphomas, not otherwise specified (PTCL, NOS). Malignant cells in AITL are predominantly CD4+CD8- and characterized by the ex- pression of T-follicular helper cell (TFH) markers such as ICOS or PD-1.2 PTCL, NOS display heterogeneous phenotypes that do not match any other category and represent about 20% of PTCL.3 Despite advances in the understanding and classification of these neoplasms over the past decades, their prognosis remains poor, with a 5-year overall survival (OS) around 30%, fostering the need to identify new ther- apeutic targets. Moreover, although immune checkpoint inhibitors that target inhibitory receptors, such as PD-1/ PD-L1 blocking agents, have been successfully used in
some hematologic malignancies,4,5 their clinical benefits in nodal PTCL are relatively modest,6,7 and several cases of hyperprogression have even been reported in patients with different PTCL,6,8 likely due to the expression of PD-1 by neoplastic cells.9
Transposing checkpoint-blockade-based immunotherapies to nodal PTCL has been hindered by our poor understanding of the types and phenotypes of immune cells recruited in response to these tumors. Studies focusing on the contri- bution of the tumor microenvironment (TME) to PTCL pro- gression reported that monocytes, as well as immunosup- pressive CD163+ macrophages, were suggested to promote a worsening of the disease,10,11 whereas high levels of B cells and dendritic cells (DC) and a high CD8/CD4 T-cell ratio were associated with better survival,12,13 although these latter findings have recently been challenged.14 Though generally of poor prognosis in most cancers,15 the proportion and prognostic value of immunosuppressive Foxp3+ regulatory T cells in PTCL are still unclear.16,17 Finally, a recent study using Cytof and scRNA-seq approaches revealed the ex-
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Correspondence: Y. Grinberg-Bleyer yenkel.grinberg-bleyer@inserm.fr
Received: Accepted: Early view:
October 16, 2023. May 17, 2024.
May 30, 2024.
https://doi.org/10.3324/haematol.2023.284448
©2025 Ferrata Storti Foundation Published under a CC BY-NC license