Spatial mapping of pre-cancerous fibrosis niche of the chronic hepatitis B

Aim: Understanding the pre-cancerous microenvironment of hepatocellular carcinoma (HCC) is key to developing a cancer prevention strategy. The study aims to clarify the cellular microenvironment associated with future HCC development by using a spatial omics approach.
Methods: We used HCC specimens resected from the patients with chronic hepatitis B. Liver tissues from the same patient were analyzed with the GeoMx spatial transcriptome, single-cell RNA-sequencing (scRNA-seq), multiplex IHC, and in situ hybridization. GeoMx acquired stromal area-specific transcriptomes across the tissue, including Tumor and non-tumor areas. The GeoMx and scRNA-seq were integratively analyzed (SpatialDeconvolution). Liver tissue transcriptome obtained from a publicly available database was used for the correlation analysis between the gene signature and patients' prognosis.
Results: SpatialDeconvolution elucidated the immune/vascular/mesenchymal populations at stromal areas (fibrosis niche). The fibrosis niche revealed a unique pattern depending on the proximity to cancer and hepatocytes' HBV infection status. The peri-cancer fibrosis niche contained the most immunosuppressive populations (e.g., Exhausted T cells). In the background non-tumor tissue, immunosuppressive populations accumulated more around HBsAg-negative hepatocytes than HBsAg-positive hepatocytes. Correlation analysis with patients' prognosis indicated that the early recurrence after the surgical resection of HCC was associated with fibrosis niche signature around the HbsAg-negative area.
Conclusion: Spatial omics elucidated the heterogeneous fibrosis niche associated with HCC pathophysiology. Immunosuppressive populations accumulated around HbsAg-negative areas could be a therapeutic target for preventing the future development of HCC.