Cancer Immunol Res. 2025 Oct 29. doi: 10.1158/2326-6066.CIR-25-0677. Online ahead of print.

ABSTRACT

Patients with Sezary syndrome (SS), the aggressive leukemic variant of cutaneous T cell lymphoma (CTCL), have few therapeutic options and a poor prognosis. We previously showed that the IL4/IL13 signaling pathway impacts SS tumorigenesis. Here, we investigated the potential therapeutic effect of REGN668 (dupilumab), a monoclonal antibody 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 SS patients. 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. Further, dupilumab reverts the immunosuppressive phenotype of non-clonal T lymphocytes and myeloid cells in the SS tumor microenvironment, including the function of MDSCs as well as Th2 and exhaustion pathways. Our study provides new insights into SS pathogenesis and a framework for precision therapies. While case reports have raised concerns over dupilumab-induced CTCL, these appear 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.

PMID:41159943 | DOI:10.1158/2326-6066.CIR-25-0677