Dupilumab unmasking cutaneous γδ T cell lymphoma through promoting tumorous T cell aggressiveness and microenvironment reprogramming

Summary: Abstract Body: Recent case reports suggest that dupilumab, a monoclonal antibody blocking interleukin-4 and interleukin-13, indicated for allergic disease, may unmask or promote cutaneous T-cell lymphoma (CTCL), though the mechanism remains unknown. Here, we report a rare case of a patient with a 3-year history of eczema who developed CD4+ γδ T cell lymphoma with severe peripheral blood involvement after 3 months of dupilumab. To explore the underlying mechanisms, we performed single-cell sequencing on the patient’s PBMCs and treated PBMCs ex vivo with IL-4, IL-13, with and without dupilumab. We identified a CD4+ Vγ2/5+ Vδ1+ non-cytotoxic skin-resident T cell lymphoma involving both skin and peripheral blood. IL4R was widely expressed across all cell types, while IL13RA1 was restricted to monocytes. Dupilumab reduced IL4R expression and increased IL13RA1 expression in corresponding cell types. Notably, dupilumab significantly increased the proliferation of tumorous T cells, which exhibited a markedly higher γδ T-cell aggressive score and upregulated exhaustion markers. The interferon response pathway was enriched after dupilumab, a pathway known to be linked to aggressiveness and poor prognosis in γδ T-cell lymphoma. Further analysis of the immune microenvironment revealed that in the IL-4-treated group, CD8+ T cells under dupilumab treatment showed reduced cytotoxicity (marked by decreased GZMA, GZMB and GZMK) and increased exhaustion. Meanwhile, in the IL-13-treated group, the phenotype of CD8+ T cells remained unchanged under dupilumab treatment, consistent with the monocyte-restricted expression of IL13RA1. Additionally, dupilumab upregulated genes (S100A8, S100A9, IL15, IL1B, CD274, IDO1) in monocytes that are known to promote tumor progression. This case provides the first evidence that dupilumab promotes tumor progression in T cell lymphoma. However, whether its effects are confined to γδ T-cell lymphoma remains unknown. These findings offer novel insights into dupilumab-associated CTCL and may guide future clinical monitoring strategies. Mingjia Li¹, Yu Xiao¹, Yi Jiang¹, Yang Wang¹ 1. Dermatology and Venereology, Peking University First Hospital, Beijing, Beijing, China. Translational Studies: Cell and Molecular Biology