IL4Rα blockade inhibits proliferation of malignant lymphocytes and the immunosuppressive tumor microenvironment of mycosis fungoides
Alyxzandria M Gaydosik, Alyson Wang, Jishnu Das, Brigit Lapolla, Oleg E Akilov, Larisa J Geskin, Patrizia FuschiottiBackground
Limited therapeutic options are available for patients with advanced-stage mycosis fungoides (MF), and the 5-year survival rate is 25%. Due to its critical role in MF pathogenesis, the IL4/IL13 pathway presents a promising target for treatment. Here, we analyzed blocking of IL4Rα, the common subunit of the IL4 and IL13 receptors, within the advanced-stage MF cutaneous tumor microenvironment (TME).
Methods
Cellular Indexing of Transcriptomes and Epitopes by sequencing was employed to assess the transcriptional profile of the cells expressing the IL4 and IL13 receptors within the advanced MF TME. We combined IL4Rα inhibition by REGN668 (dupilumab) in ex vivo skin explants from advanced MF patients with single-cell transcriptome and machine learning analysis to identify the molecular mechanisms of IL4Rα signaling within the MF skin lesions. Parallel analysis of the T cell immune repertoire allowed identification of the expanded malignant clone within each MF sample. Multicolor immunofluorescence microscopy was employed to validate molecular findings.
Results
REGN668 inhibits patient-specific processes in malignant lymphocytes; however, we also identified downregulation of common pathways among patient samples, including those associated with cell cycle progression, PI3K/AKT signaling, janus kinase (JAK)/Signal Transducer and Activator of Transcription (STAT) signaling, DNA damage/repair, and TP53 regulation. Furthermore, we showed that IL4Rα blockade in the TME of advanced MF downregulates multiple immunosuppressive pathways associated with myeloid-derived suppressor cells and LAMP3 + dendritic cell recruitment and function, cytokine production, and antigen presentation in B cells, as well as differentiation and degranulation of mast cells.
Conclusions
These results provide new insights into advanced MF tumorigenesis and show that the effects of IL4Rα blockade are specific to the STAT6 pathway, inhibiting proliferation of malignant lymphocytes, as well as repressing several immunosuppressive mechanisms 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 will be important for developing new therapeutic strategies against this disease.