Mogamulizumab induces long-term immune restoration and reshapes tumour heterogeneity in Sézary syndrome

Background: Mogamulizumab, an anti-CCR4 monoclonal antibody, has been shown to increase progression-free survival in cutaneous T-cell lymphoma.

Objectives: We hypothesized that besides the targeted depletion of Sézary cells (SCs), mogamulizumab may reshape the immune tumour microenvironment.

Methods: Both malignant and benign compartments from 26 patients with B2 stage Sézary syndrome before mogamulizumab initiation were prospectively analysed using KIR3DL2 and TCRVβ markers, serological markers and molecular assessments of clonality.

Results: Prior to mogamulizumab, the benign subset of CD4⁺ T cells displayed exhausted phenotypes, with an increased gradient in programmed death-1, TIGIT, DNAM-1, CD27, CD28 and CD70 expression from age-matched controls to patients' benign CD4⁺ T cells and to SCs. All patients presented SCs with heterogeneous phenotypes, and differential expression of individual markers was found within distinct malignant subsets. Early complete blood response was observed in 17 of 26 patients and was associated with higher baseline CCR4 expression. A drastic decrease in benign T cells and activated regulatory T-cell counts was observed during the first 4 weeks. Long-term follow-up revealed the emergence of an immune restoration involving CD8⁺ and naive and stem memory CD4⁺ T cells, with almost complete disappearance of exhausted lymphocytes. Development of resistance or tumour escape to mogamulizumab was associated with the emergence of CCR4^- SCs in blood and skin, displaying significant changes in their heterogeneity patterns, and not explained only by mutations within CCR4 coding regions.

Conclusions: Mogamulizumab likely contributes to the restoration of efficient immunity and reshapes not only the malignant lymphocyte subset but also the benign subset. These results have potential implications for optimal therapeutic sequences and/or combinations. What is already known about this topic? Management of Sézary syndrome (SS) involves successive therapies that participate as cause and consequence in the emergence of resistant clones, on a background of immunodeficiency. We and others have reported the complex and dynamic heterogeneity of Sézary cells (SCs) during disease progression. Mogamulizumab therapy, by targeting the skin-homing receptor CCR4, mainly expressed by SCs, has been shown to increase progression-free survival in patients with SS. What does this study add? Using multicolour flow cytometry, we provide quantification of CCR4 and immune checkpoint molecules on malignant SCs and benign CD4⁺ T cells from patients with SS, separated using KIR3DL2 and TCRVβ expression. Mogamulizumab is not only aimed at eradicating malignant SCs but potentially contributes to the restoration of efficient immunity. Tumour escape is associated with the emergence of CCR4^- SCs, not explained only by mutations within CCR4 coding regions.