Deep Spatial Sequencing Revealing Differential Immune Responses in Human Hepatocellular Carcinoma

Area of Science:

• Oncology
• Genomics
• Immunology

Background:

• Hepatocellular carcinoma (HCC) is a highly lethal and heterogeneous human cancer.
• Understanding the spatial heterogeneity and cellular interactions within the tumor microenvironment is crucial for deciphering HCC development.

Purpose of the Study:

• To investigate the spatial gene expression patterns and cellular interactions in HCC using ultra-depth spatial sequencing.
• To compare the heterogeneity of HCC with benign liver tissues.
• To explore the impact of immune cell infiltration on surrounding cells in HCC versus benign liver.

Main Methods:

• Performed ultra-depth (~1 million reads per spot) spatial sequencing on a case of HCC and adjacent benign liver tissue.
• Identified distinct spatial expression clusters and immune cell-enriched regions.
• Analyzed gene expression alterations in cells adjacent to immune-enriched spots.

Main Results:

• Identified 16 distinct, spatially contiguous gene expression clusters in HCC, contrasting with minimal heterogeneity in benign liver.
• Observed numerous immune cell-enriched spots in both HCC and benign tissues.
• Found significant and broader gene expression alterations in HCC cells near immune cells compared to muted responses in benign liver cells.
• Standard-depth sequencing failed to detect many significant genes and pathways identified by deep sequencing.

Conclusions:

• Ultra-depth spatial sequencing can reveal previously unrecognized spatial heterogeneity and gene expression patterns in HCC.
• HCC cells exhibit a more intense and broader response to nearby immune cells than benign liver cells.
• Deep spatial sequencing is essential for uncovering complex mechanisms in liver cancer development and immune interactions.