Unleashed monocytic engagement in Sezary syndrome during the combination of anti-CCR4 antibody with type I interferon.
Abstract
Sezary syndrome is an aggressive leukemic expansion of skin derived malignant CD4+ T cells. Drug monotherapy often results in disease relapse due to the heterogenous nature of malignant CD4+ T cells, but how therapies can be optimally combined remains unclear due to limitations in understanding the disease pathogenesis. We identified immunologic transitions that interlink mycosis fungoides (MF) with Sezary syndrome (SS) using single-cell transcriptome analysis in parallel with high-throughput TCR sequencing. Nascent peripheral CD4+ T cells acquired a distinct profile of transcription factors and trafficking receptors that gave rise to antigenically mature Sezary cells. The emergence of malignant CD4+ T cells coincided with the accumulation of dysfunctional monocytes with impaired Fc -dependent phagocytosis, decreased responsiveness to cytokine stimulation and limited repertoire of intercellular interactions with Sezary 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 Sezary cells in vitro. In turn, co-administration of interferon- with the FDA-approved anti-CCR4 antibody, mogamulizumab, in patients with SS induced marked depletion of peripheral malignant CD4+ T cells. Importantly, residual CD4+ T cells following Sezary 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.
Authors: | Jiang TT, Kruglov O, Akilov OE, |
---|---|
Journal: | Blood Adv . 2024 May 28;8(10):2384-2397. doi: 10.1182/bloodadvances.2023010043. |
Year: | 2024 |
PubMed: | PMID: 38489234 (Go to PubMed) |