Identification of Fibroinflammatory and Fibrotic Transcriptomic Subsets of Human Cutaneous Sclerotic Chronic Graft-Versus-Host Disease

ABSTRACT Cutaneous sclerotic chronic graft-versus-host disease (cGVHD) is a common and highly morbid complication of allogeneic hematopoietic stem cell transplantation (HSCT). We identified genes that are significantly upregulated in the skin of sclerotic cGVHD patients (n = 17) compared to HSCT patients without sclerotic cGVHD (n = 9) by bulk RNA sequencing. This revealed two transcriptomic groups of affected patients: those with fibrotic and inflammatory/Th1 gene expression, the fibroinflammatory group, and those with predominantly fibrotic/TGFβ-associated expression, the fibrotic group. This transcriptomic heterogeneity was also associated with histopathologic heterogeneity, with the fibroinflammatory sub-cluster showing more histopathologic features of epidermal cGVHD and inflammation. Further study will help elucidate if these gene expression and histopathologic findings can be used to tailor treatment decisions. Multiple highly induced genes in the skin ( SFRP4, SERPINE2, COMP ) were also found to be significantly induced in sclerotic cGVHD patient plasma (n = 16) compared to control HSCT patients without sclerotic cGVHD (n = 17), suggesting these TGFβ and Wnt pathway mediators as candidate blood biomarkers of disease.