IL4Ra blockade inhibits proliferation of malignant lymphocytes and the immunosuppressive tumor microenvironment of mycosis fungoides

The IL4 and IL13 receptors are highly expressed in the mycosis fungoides (MF) cutaneous tumor microenvironment (TME). By combining single-cell RNA sequencing with inhibition of IL4Ra with Dupilumab (REGN668), a monoclonal antibody that targets the common subunit of the IL4 and IL13 receptors, we have identified the genes and pathways regulated by IL4/IL13 signaling in the MF TME. We found that Dupilumab inhibits patient-specific processes in malignant lymphocytes, and we also identified downregulation of common pathways among patient samples including those associated with cell cycle progression, PI3K/AKT signaling, JAK/STAT signaling, DNA damage/repair, and TP53 regulation. Using ex vivo skin explants assays from advanced MF skin tumors we demonstrated that Dupilumab inhibits proliferation of MF malignant lymphocytes without affecting their survival. Furthermore, we showed that IL4Ra blockade in the TME of advanced MF downregulates multiple immunosuppressive pathways associated with myeloid-derived suppressive cell and LAMP3+ dendritic cell recruitment and function, cytokine production and antigen presentation in B cells as well as differentiation, and degranulation of mast cells. These results provide new insights into advanced MF tumorigenesis including the nature of Dupilumab interactions within the MF TME. However, the extensive genetic, transcriptional, and functional heterogeneity across MF patients indicates that inhibition of multiple driver pathways and a personalized therapeutic approach, which may include Dupilumab, will be essential for developing new therapeutic strategies against this incurable disease.