Abstract
BACKGROUND: Chronic cutaneous graft-versus-host disease (ccGVHD) is a debilitating complication of allogeneic haematopoietic stem cell transplantation, manifesting as either sclerotic or lichenoid eruptions (lGVHD). Although frequent, the pathogenesis of lGVHD remains mainly unknown and represents a therapeutic challenge. OBJECTIVES: This study aims to decipher the immunological mechanisms underlying lichenoid GVHD and to evaluate the effect of blocking the Type I interferons (IFN-I) pathway in a mice model of ccGVHD on local inflammation. METHODS: First, we performed single-cell gene expression analysis (scRNA-Seq) of human lGVHD skin samples (n = 3) compared with healthy control (n = 4) and analysed the distribution and inflammatory signatures of immune cells. Results were confronted with bulk-RNA-Seq data of an independent cohort of lGVHD (n = 8) previously published by our group to compare the predicted immune population within lGVHD skin through deconvolution analyses. The IFN-I score was assessed through quantitative PCR on lGVHD lesions (n = 13) compared with HC (n = 10). Secondly, we analysed publicly available skin microarray data from a mouse model of ccGVHD, in which allografted mice were treated with an anti-IFNAR1 antibody targeting the Type I interferon receptor. RESULTS: ScRNA-Seq analysis of human immune cells revealed a strong Type I and II interferons signature in lGVHD skin, along with an increased expression of T(h2)/T(h17) and activation markers in T cells and macrophages, respectively. Consistent with our human data, murine skin GVHD samples were characterized by interferon and allograft inflammatory responses, which were greatly prevented by early infusions of anti-IFNAR1 antibody after allograft. Bioinformatic analyses highlighted interferons, along with T(h2) and T(h17) markers, as putative key regulators in mice skin inflammation that were also diminished or abrogated consequently to early anti-IFNAR1 antibody infusions. CONCLUSIONS: Together, our data suggests that interferon pathways, and in particular Type I via IFNAR1, may be promising therapeutic targets for the treatment of lichenoid chronic GVHD.