IL4/IL13 Inhibition via Dupilumab Reduces Malignant T-cell Proliferation and Promotes Antitumor Immunity in Sézary Syndrome

Patients with Sézary syndrome, the aggressive leukemic variant of cutaneous T-cell lymphoma, have few therapeutic options and a poor prognosis. We previously showed that the IL4/IL13 signaling pathway affects Sézary syndrome tumorigenesis. In this study, we investigated the potential therapeutic effect of REGN668 (dupilumab), an mAb that blocks the IL4/IL13 pathway by targeting the receptors' common IL4Rα subunit. We used single-cell RNA sequencing coupled with T-cell immune repertoire analysis to define the transcriptional changes and molecular mechanisms associated with REGN668 treatment in malignant and reactive T lymphocytes, as well as in monocytes and dendritic cells from the peripheral blood of patients with Sézary syndrome. Although REGN668 induced patient-specific transcriptional changes in malignant lymphocytes, it also downregulated several pro-tumorigenic processes that were shared across patient samples, including cell division, DNA damage/repair, autophagy, and T-cell signaling pathways. Ex vivo studies demonstrated that REGN668 inhibits proliferation of malignant lymphocytes more efficiently than blocking either IL4 or IL13 signaling alone. Furthermore, dupilumab reverts the immunosuppressive phenotype of non-clonal T lymphocytes and myeloid cells in the Sézary syndrome tumor microenvironment, including the function of myeloid-derived suppressor cells as well as Th2 and exhaustion pathways. Our study provides new insights into Sézary syndrome pathogenesis and a framework for precision therapies. Although case reports have raised concerns over dupilumab-induced cutaneous T-cell lymphoma, these seem attributable to initial misdiagnoses rather than a direct causative effect. Our findings indicate that dupilumab exerts pathway-specific effects and could contribute to a multi-pathway therapeutic approach.