Dupilumab inhibits proliferation of malignant lymphocytes in Sezary syndrome and boosts anti-tumor immunity

Patients with Sezary syndrome (SS), 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 is critical in SS tumorigenesis. Here we investigated the potential therapeutic effect of inhibiting IL4/IL13 signaling with REGN668 (Dupilumab), a monoclonal antibody that blocks the IL4/IL13 pathway by targeting IL4Rα, the common subunit of the IL4 and IL13 receptors. Using recent advances in single-cell RNA sequencing we defined 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. We observed variable responses across patient samples and downregulation of patient-specific pathways in malignant and reactive immune cells. Significantly, we found that REGN668 downregulates expression of common pro-tumorigenic processes in malignant lymphocytes, including cell division, DNA damage/repair, autophagy, and various pathways associated with T-cell signaling. A key finding from functional ex vivo studies was that REGN668 inhibits proliferation of malignant lymphocytes more efficiently than blocking either IL4 or IL13 signaling alone. Furthermore, we found that Dupilumab also 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. Although some case reports have cast doubt on the efficacy of Dupilumab in treating SS patients, our results suggest that the effects of Dupilumab are pathway-specific and that it may be a critical component of a multi-pathway treatment.