Page 147 - Haematologica Vol. 110 - January 2025

ARTICLE - Immune microenvironment in nodal PTCL
wide debate and there is room for improvement.30,31 Differ- ent strategies have been used to create anti-CTLA4 IgG1 mAb with strong Treg-depleting properties and anti-tumor effects in preclinical models32,33 which deserve attention for PTCL therapy. MEDI-570, an afucosylated IgG1 anti-ICOS mAb, was shown to induce T-cell depletion in cynomolgus monkeys;34 a phase I trial reported positive signs of activ- ity in AITL patients.35 In addition to these T-cell-targeting agents, NKG2A also appears to be an interesting target in PTCL as its expression was largely restricted to NK cells. As blocking anti-NKG2A mAb are currently under clinical evaluation in solid cancers,36 they may represent a future therapeutic avenue in PTCL.
In addition to these traditional immune checkpoints, our data highlight CD39 as a promising target in nodal PTCL, both through its prognostic value and its potential thera- peutic targeting. The combined action of CD39 and CD73 that leads to the production of adenosine have been ex- tensively described for their tumor-promoting functions in solid cancers.21 CD39 inhibition reinvigorates cytotoxic T-cell activity in preclinical models of melanoma or sarcoma, among others.37 CD39 expression also increases in different hema- tologic malignancies, including T-cell-derived cancers such as adult T-cell leukemia / lymphoma or Sezary syndrome.38,39 High expression of CD39 was shown to be associated with poor prognosis in diffuse large B-cell lymphoma and mul- tiple myeloma.40,41 CD39 expression on T cells is correlated with disease severity in patients with chronic lymphocyt- ic leukemia.42,43 Because of this association with tumor progression, the therapeutic potential of CD39 inhibition has mainly been evaluated in blood cancers. For example, mAb targeting CD39 potentiate the therapeutic efficacy of T-cell transfer in a humanized model of B-cell lymphoma,44 whereas ARL67156 and POM-1, two ectonucleotisase inhib- itors with high affinity for CD39, enhance T-cell function in follicular lymphoma and multiple myeloma patient samples, respectively.41,45 CD73 or A2AR inhibition enhances non-tu- moral T-cell proliferation in Sezary syndrome in vitro.46 Our data now extend the tumor-promoting properties of CD39 to nodal PTCL. We propose that CD39 expression could be assessed by immunohistochemistry and/or flow cytometry as a potent prognostic factor in AITL. Moreover, patients with PTCL may benefit from the CD39-blocking agents currently under clinical development for other cancers.
Disclosures
EM reports research funding from Astra-Zeneca. PG reports consultancy for Gilead and Takeda, and research funding
References
1. Campo E, Jaffe ES, Cook JR, et al. The International Consensus Classification of Mature Lymphoid Neoplasms: a report from the Clinical Advisory Committee. Blood. 2022;140(11):1229-1253.
P. Stephan et al. from Alderan, Innate Pharma, Sanofi, and Takeda. FL re-
ports research funding from Institut Roche and travel grant from Gilead. LdL reports consultancy for AbbVie, Bayer, Bio Ascend, Lunaphore, Novartis. EB reports consultancy or lecture fees from Incyte, Roche, Takeda, ADCTherapeutics, Novartis, Kite/GILEAD, Miltenyi, Janssen, and Sanofi, travel expense reimbursement from Roche, Gilead, and Abbvie, and research funding from Agmen, Bristol-Myers Squibb, and Daiichi Sankyo. PSu reports consultancy or lecture fees from Gilead/Kyte, Janssen Cylag, BMS/Cellgene, and Abbvie, and research funding from Astra-Zeneca and Servier. The other authors have no conflicts of interest to disclose.
Contributions
PSt, JP, AV, MBarb, TA, MBard and GT performed experiments and analyzed data. MP, MG, JC, EM, PG, LDL, EB, LG and YGB analyzed data. PG, FL, LDL, EB, PSu, LG and ATG se- lected patient samples and confirmed the original diagnosis through pathological analyses. YGB supervised the study, wrote the paper, and secured funding.
Acknowledgments
We thank the CeVi_Collection group (https://experts-recher- che-lymphome.org/calym/explorer-les-ressources-du-con- sortium/collection-cevi/centres-participants-a-la-collec- tion-cevi/) from the CALYM Carnot Institute funded by the French National Research Council (ANR) for providing cell suspension samples from PTCL patients. We thank the biological resource centers of Montpellier, Toulouse, and Creteil for providing the fixed tissue samples obtained at diagnosis, used for re-assessment of the original diagnosis. We are grateful to Maud Plaschka (CCRI, Vienna, Austria) for bioinformatics analyses. We thank Pierre Milpied (CIML, Marseille, France), as well as all members of the lab, for helpful discussions on the project.
Funding
This project was funded by grants from la Ligue contre le Cancer, the ATIP-Avenir funds, and the Laboratory of Ex- cellence (LabEx) Dev2Can (ANR-10-LABX-0061), to YGB. PS was supported by a scholarship from the Fondation pour la Recherche Médicale (FRM). AV was supported by a fellowship from the Association pour la Recherche contre le Cancer (ARC) Foundation.
Data-sharing statement
All raw or analyzed data will be made available upon rea- sonable request by e-mail to the corresponding author.
2. Fujisawa M, Chiba S, Sakata-Yanagimoto M. Recent progress in the understanding of angioimmunoblastic T-cell lymphoma. J Clin Exp Hematop. 2017;57(3):109-119.
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