CD39, CD73, and CD38 track tumor burden and reveal immune remodeling during mogamulizumab therapy in Sézary syndrome

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.