Unleashed monocytic engagement in Sézary syndrome during the combination of anti-CCR4 antibody with type I interferon

Sézary syndrome (SS) is an aggressive leukemic expansion of skin-derived malignant CD4+ T cells. Drug monotherapy often results in disease relapse because of the heterogenous nature of malignant CD4+ T cells, but how therapies can be optimally combined remains unclear because of limitations in understanding the disease pathogenesis. We identified immunologic transitions that interlink mycosis fungoides with SS using single-cell transcriptome analysis in parallel with high-throughput T-cell receptor sequencing. Nascent peripheral CD4+ T cells acquired a distinct profile of transcription factors and trafficking receptors that gave rise to antigenically mature Sézary cells. The emergence of malignant CD4+ T cells coincided with the accumulation of dysfunctional monocytes with impaired fragment crystallizable γ-dependent phagocytosis, decreased responsiveness to cytokine stimulation, and limited repertoire of intercellular interactions with Sézary cells. Type I interferon supplementation when combined with a monoclonal antibody targeting the chemokine receptor type 4 (CCR4), unleashed monocyte induced phagocytosis and eradication of Sézary cells in vitro. In turn, coadministration of interferon-α with the US Food and Drug Administration-approved anti-CCR4 antibody, mogamulizumab, in patients with SS induced marked depletion of peripheral malignant CD4+ T cells. Importantly, residual CD4+ T cells after Sézary cell ablation lacked any immunologic shifts. These findings collectively unveil an auxiliary role for augmenting monocytic activity during mogamulizumab therapy in the treatment of SS and underscore the importance of targeted combination therapy in this disease.