CD39, CD73, and CD38 track tumor burden and reveal immune remodeling during mogamulizumab therapy in Sézary syndrome
4 affiliations
- 1Laboratory of Immunogenetics, Department of Medical Sciences, University of Turin, Turin, Italy
- 2Dermatologic Clinic, Department of Medical Sciences, University of Turin, Turin, Italy
- 3Department of Dermatology, Leiden University Medical Center, Leiden, The Netherlands
- 4Interdipartimental Center for Molecular Biotechnologies "Guido Tarone”, University of Turin, Turin, Italy
Abstract
Background: Sézary syndrome (SS) is an aggressive leukemic cutaneous T-cell lymphoma characterized by circulating malignant CD4+ T cells. Although mogamulizumab (Moga), an anti-CCR4 monoclonal antibody, improves progression-free survival in SS, reliable pharmacodynamic biomarkers for monitoring treatment response and relapse remain lacking. Recent evidence demonstrated that CD39, CD73, and CD38 ectonucleotidases represent tumor-intrinsic markers for SS cell identification; here, we investigated their utility for longitudinal disease monitoring during Moga therapy, while characterizing treatment-induced immune remodeling.
Methods: Peripheral blood immune cell subsets from 14 patients with SS receiving Moga were longitudinally profiled by conventional (6-color) and spectral (22-color) flow cytometry over a median follow-up of 26 months. Ectonucleotidase expression was assessed on malignant and non-malignant immune cell subsets throughout treatment, including response and relapse.
Results: In responders, residual tumor cells consistently retained their patient-specific CD39+ and/or CD73+ aberrant profiles with persistently low CD38 expression throughout treatment. Longitudinal assessment of these markers on total CD4+ T cells closely reflected hematologic disease activity, declining during response and returning to baseline levels at relapse, consistent with re-emergence of phenotypically stable malignant clones. Patients with cutaneous-only progression maintained stable circulating ectonucleotidase profiles, reflecting sustained hematologic disease control despite skin relapse. Beyond the malignant compartment, Moga induced profound immune remodeling across conventional and regulatory CD4+ T, CD8+ T, natural killer (NK), NK T cell, and B cells, with subset-specific ectonucleotidase modulation during response and relapse. Notably, re-expansion of CD39+ regulatory T cells accompanied disease progression in selected patients, contrasting with their sustained depletion in sustained responders. In contrast, in patients with primary resistance, ectonucleotidase profiles remained unchanged, while distinct resistance mechanisms were identified, including impaired Moga binding to CCR4 and reduced NK-cell CD16 expression.
Conclusions: Combined assessment of CD39, CD73, and CD38 defines a candidate pharmacodynamic biomarker signature for longitudinal monitoring of hematologic disease during Moga therapy in SS. Longitudinal profiling further reveals treatment-induced remodeling across non-malignant immune subsets associated with disease progression, supporting the integration of ectonucleotidase profiling into biomarker-driven monitoring strategies in SS.
Related
- Infection and sensitization reveal stimulus-specific immune remodeling in aged skin
- Collagen4 fluorescent protein knock-in lines reveal remodeling of cardiovascular basement membranes
- STAG2-truncating variants reveal a mosaic STAG2 inactivation pattern and compensatory mechanisms involving cohesin complex remodeling
- Multi-omics analyses reveal environmentally adaptive cell-state remodeling during human iPSC biomanufacturing
- Single‐Cell Transcriptomics and Metabolomics Reveal Glutamate Dehydrogenase as a Central Regulator of Nitrogen Metabolic Remodeling During Alkalinity Adaptation in Crustaceans
BibTeX
@article{marchisio2026cd39,
title = {{CD39, CD73, and CD38 track tumor burden and reveal immune remodeling during mogamulizumab therapy in Sézary syndrome}},
author = {Sara Marchisio and Yuliya Yakymiv and Liyun Lin and Erika Ortolan and Renata Ponti and Fenna J De Bie and Alita J Van Der Sluijs-Gelling and Valentina Pala and Ferenc Scheeren and Maarten H Vermeer and Ada Funaro and Pietro Quaglino and Simone Ribero and Gabriele Roccuzzo},
journal = {Journal for Immunotherapy of Cancer},
year = {2026},
month = nov,
doi = {10.1136/jitc-2026-016705},
url = {https://doi.org/10.1136/jitc-2026-016705},
note = {CC BY-NC 4.0},
}
RIS
TY - JOUR
TI - CD39, CD73, and CD38 track tumor burden and reveal immune remodeling during mogamulizumab therapy in Sézary syndrome
AU - Sara Marchisio
AU - Yuliya Yakymiv
AU - Liyun Lin
AU - Erika Ortolan
AU - Renata Ponti
AU - Fenna J De Bie
AU - Alita J Van Der Sluijs-Gelling
AU - Valentina Pala
AU - Ferenc Scheeren
AU - Maarten H Vermeer
AU - Ada Funaro
AU - Pietro Quaglino
AU - Simone Ribero
AU - Gabriele Roccuzzo
PY - 2026
DA - 2026/11/02
JO - Journal for Immunotherapy of Cancer
DO - 10.1136/jitc-2026-016705
UR - https://doi.org/10.1136/jitc-2026-016705
AB - Background: Sézary syndrome (SS) is an aggressive leukemic cutaneous T-cell lymphoma characterized by circulating malignant CD4+ T cells. Although mogamulizumab (Moga), an anti-CCR4 monoclonal antibody, improves progression-free survival in SS, reliable pharmacodynamic biomarkers for monitoring treatment response and relapse remain lacking. Recent evidence demonstrated that CD39, CD73, and CD38 ectonucleotidases represent tumor-intrinsic markers for SS cell identification; here, we investigated their utility for longitudinal disease monitoring during Moga therapy, while characterizing treatment-induced immune remodeling. Methods: Peripheral blood immune cell subsets from 14 patients with SS receiving Moga were longitudinally profiled by conventional (6-color) and spectral (22-color) flow cytometry over a median follow-up of 26 months. Ectonucleotidase expression was assessed on malignant and non-malignant immune cell subsets throughout treatment, including response and relapse. Results: In responders, residual tumor cells consistently retained their patient-specific CD39+ and/or CD73+ aberrant profiles with persistently low CD38 expression throughout treatment. Longitudinal assessment of these markers on total CD4+ T cells closely reflected hematologic disease activity, declining during response and returning to baseline levels at relapse, consistent with re-emergence of phenotypically stable malignant clones. Patients with cutaneous-only progression maintained stable circulating ectonucleotidase profiles, reflecting sustained hematologic disease control despite skin relapse. Beyond the malignant compartment, Moga induced profound immune remodeling across conventional and regulatory CD4+ T, CD8+ T, natural killer (NK), NK T cell, and B cells, with subset-specific ectonucleotidase modulation during response and relapse. Notably, re-expansion of CD39+ regulatory T cells accompanied disease progression in selected patients, contrasting with their sustained depletion in sustained responders. In contrast, in patients with primary resistance, ectonucleotidase profiles remained unchanged, while distinct resistance mechanisms were identified, including impaired Moga binding to CCR4 and reduced NK-cell CD16 expression. Conclusions: Combined assessment of CD39, CD73, and CD38 defines a candidate pharmacodynamic biomarker signature for longitudinal monitoring of hematologic disease during Moga therapy in SS. Longitudinal profiling further reveals treatment-induced remodeling across non-malignant immune subsets associated with disease progression, supporting the integration of ectonucleotidase profiling into biomarker-driven monitoring strategies in SS.
SN - 2051-1426
ER -