Spatial Transcriptomics Reveals Distinct Tissue Niches Linked with Steroid Responsiveness in Acute Gastrointestinal GVHD.

Severe acute graft-versus-host disease (aGVHD) is associated with significant mortality and morbidity, especially in steroid-resistant (SR) cases. Spatial transcriptomic technology can elucidate tissue-based interactions in vivo and possibly identify predictors of treatment response. Tissue sections from thirty-two treatment naïve patients with biopsy-confirmed lower gastrointestinal aGVHD were obtained. The GeoMxTM digital spatial profiler was used to capture transcriptome profiles of >18,000 genes from different foci of immune infiltrates, colonic epithelium, and vascular endothelium. Each tissue compartment sampled showed two distinct clusters that were analyzed for differential expression and spatially resolved correlation of gene signatures. Classical cell mediated immunity (CMI) signatures, normal differentiated epithelial cells, and inflamed vasculature dominated foci sampled from steroid-sensitive cases. In contrast, a neutrophil predominant non-canonical inflammation with regenerative epithelial cells and some indication of angiogenic endothelial response were over-represented in areas from SR cases. Evaluation of potential prognostic biomarkers identified USP17L family of genes as being differentially expressed in immune cells from patients with worsened survival. In summary, we demonstrate distinct tissue niches with unique gene expression signatures within lower gastrointestinal tissue from patients with aGVHD and provide evidence of a potential prognostic biomarker.