Lichenoid graft-versus-host disease shows a high interferon score, with IFNAR1 inhibition preventing skin...

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.

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.

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.

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.

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.