Single-cell and spatial atlas of steatotic liver-related hepatocellular carcinoma

Prawira, A.; Xu, H.; Leow, W. Q.; Otsuka, M.; Chen, Z.; Rahbari, M.; Hazirah, S. N.; Wasser, M.; Chung, A.; Goh, B. K. P.; Chow, P. K.-H.; Albani, S.; Lee, J.; Lim, T.; Zhai, W.; Dan, Y. Y.; Goh, G.; Tai, D.; DasGupta, R.; Heikenwalder, M.; Chen, J.; Chew, V.

doi:10.1101/2024.05.09.593073

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bioRxiv · 10.1101/2024.05.09.593073

Single-cell and spatial atlas of steatotic liver-related hepatocellular carcinoma

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Abstract

Steatotic liver disease-related hepatocellular carcinoma (SLD-HCC) poses significant challenges in liver cancer management. Our current study investigates the tumor microenvironment (TME) of SLD-HCC using single-cell transcriptomic, proteomic and spatial transcriptomic analyses. We identified altered immune-related and lipid metabolism pathways, particularly in regulatory T cells (Tregs) and cancer-associated fibroblasts (CAFs) within the SLD-HCC microenvironment, suggesting distinct cellular adaptations to a high-fat TME and general immunosuppression. Cytometry by time-of-flight revealed a cold and immunosuppressive TME depleted with CD8+ T cells and enriched with Tregs, while spatial transcriptomics uncovered a unique spatial architecture with Treg/CAF clusters specifically located at the tumor margins in SLD-HCC. Crucially, we identified Treg-CAF interactions as a key mediator associated with lack of response to immunotherapy in SLD-HCC. Our findings highlight the intricate immune dynamics of SLD-HCC, indicating potential therapeutic targets to counteract immune evasion and restore anti-tumor immunity in SLD-HCC. HighlightsO_LIThe TME of SLD-HCC exhibits altered immune and lipid pathways C_LIO_LIImmunosuppressive SLD-HCC TME is depleted with CD8+ T cells and enriched with Tregs C_LIO_LISLD-HCC has a unique spatial architecture with Treg-CAF clusters at tumor margins C_LIO_LITreg-CAF interaction via TNFSF14-TNFRSF14 axis mediates immunotherapy resistance C_LI

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Prawira, A., Xu, H., Leow, W. Q., Otsuka, M., Chen, Z., Rahbari, M., Hazirah, S. N., Wasser, M., Chung, A., Goh, B. K. P., Chow, P. K.-H., Albani, S., Lee, J., Lim, T., Zhai, W., Dan, Y. Y., Goh, G., Tai, D., DasGupta, R., Heikenwalder, M., Chen, J., Chew, V.. 2024-05-14. Single-cell and spatial atlas of steatotic liver-related hepatocellular carcinoma. https://doi.org/10.1101/2024.05.09.593073

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