USP17L RNA in immune cells: A potential biomarker in gut GvHD

Severe acute graft-versus-host disease (GvHD) of the lower gastrointestinal (GI) tract causes significant rates of morbidity and mortality, with steroid-refractory gut GvHD having a particularly poor prognosis.

Recently, Koyama et al.¹ published an article in Blood exploring the overexpression of ubiquitin-specific protease 17 (USP17L) RNA in immune/hematopoietic cells (anti-CD45) as a predictor of poor survival outcomes in lower GI acute GvHD, indicating its potential as a prognostic biomarker.¹ In the original study, GI tract biopsies were analyzed using spatial transcriptomics at GvHD onset.²

Method¹

GI tract biopsy samples were obtained from 32 patients before systemic treatment, followed by spatial transcriptomic analysis conducted using Nanostring GeoMx Digital Spatial Profiler. Hematoxylin and eosin staining were used to create a section for pathologic grading, with a second section created for the GeoMx platform for observation of cell subsets. Photocleavable gene barcodes were then bonded to RNA probes and released via ultraviolet light projection, collected into a single well of a 96-well plate, and quantified with next-generation sequencing.

Findings

During analysis, high-grade pathology and steroid resistance were seen on immune cells (IC), with the IC1 cluster exhibiting increased expression of USP17L family genes.¹ It was also observed that USP17L3, USP177, USP17L11, USP17L12, USP17L151, and USP17L7 were the most significant genes in patients experiencing non-relapse death within 6 months of lower GI acute GvHD diagnosis, with certain genes being overrepresented in the IC1 niche.²

There were discrepancies in results between both assays, with the Nanostring GeoMx indicated a moderate positive correlation between USP17L family RNA and the multi-region analysis with NanoString GeoMX recognizing the prognostic value of combined USP17L genes.² Additionally, the quantitative USP17L isoform RNA in situ hybridization assay, which separated strong and weak positivity, was not prognostic; heterogenous staining of biopsies indicated potential issues that contributed to the differences in these assays.²

Conclusion

From this study, it was established that higher expression of genes from the USP17L family may be correlated with higher non-relapse mortality and lower overall survival in this patient group; however, this study cannot assign any causative relationship to outcomes. Considering the lack of information regarding the functional role of USP17L genes in immune cells, further clinical trials are warranted to verify presence of USP17L as a biomarker in GI biopsies.