Article Text
Abstract
Objective Hepatocellular carcinoma (HCC) tumour microenvironment (TME) is highly complex with diverse cellular components organising into various functional units, cellular neighbourhoods (CNs). And we wanted to define CN of HCC while preserving the TME architecture, based on which, potential targets for novel immunotherapy could be identified.
Design A highly multiplexed imaging mass cytometry (IMC) panel was designed to simultaneously quantify 36 biomarkers of tissues from 134 patients with HCC and 7 healthy donors to generate 562 highly multiplexed histology images at single-cell resolution. Different function units were defined by topological analysis of TME. CN relevant to the patients’ prognosis was identified as specific target for HCC therapy. Transgenic mouse models were used to validate the novel immunotherapy target for HCC.
Results Three major types of intratumour areas with distinct distribution patterns of tumorous, stromal and immune cells were identified. 22 cellular metaclusters and 16 CN were defined. CN composed of various types of cells formed regional function units and the regional immunity was regulated reversely by resident Kupffer cells and infiltrating macrophages with protumour and antitumour function, respectively. Depletion of Kupffer cells in mouse liver largely enhances the T cell response, reduces liver tumour growth and sensitises the tumour response to antiprogrammed cell death protein-1 treatment.
Conclusion Our findings reveal for the first time the various topological function units of HCC TME, which also presents the largest depository of pathological landscape for HCC. This work highlights the potential of Kupffer cell-specific targeting rather than overall myeloid cell blocking as a novel immunotherapy for HCC treatment.
- hepatocellular carcinoma
- immunotherapy
- macrophages
Data availability statement
Data are available on reasonable request. Data relevant to this study are included in the supplementary information. The raw data are available on reasonable request. Please contact corresponding author, Professor Tingbo Liang, email: liangtingbo@zju.edu.cn.
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Data availability statement
Data are available on reasonable request. Data relevant to this study are included in the supplementary information. The raw data are available on reasonable request. Please contact corresponding author, Professor Tingbo Liang, email: liangtingbo@zju.edu.cn.
Footnotes
JS and JZ contributed equally.
Contributors Conceptualisation: Jianpeng Sheng and Tingbo Liang. Methodology: Jianpeng Sheng, Junlei Zhang, Jianghui Tang, Xun Wang, Jiangchao Wu, Jinyuan Song, Yinan Shen, Hui Zhang, Taohong Li and Liang Wen. IMC panel: Jianpeng Sheng, Junlei Zhang and Qi Zhang. Patient sample isolation: Jianfeng Wang, Xueli Bai and Tingbo Liang. Hyperion operation: Jingxia Rong and Yaxing Zhao. Pathological support: Fei Chen. Data analysis: Jianpeng Sheng and Junlei Zhang. Bioinformatic analysis: Lin Wang and Yaxing Zhao. Writing: Jianpeng Sheng, Junlei Zhang and Tingbo Liang. Editing: Jianpeng Sheng, Xueli Bai, Zhimin Lu and Tingbo Liang. Supervision: Jianpeng Sheng and Tingbo Liang. Funding acquisition: Jianpeng Sheng, Qi Zhang, Xueli Bai and Tiangbo Liang.
Funding This work was supported by the National Key Research and Development Program of China (grant 2019YFA0803000 to Jianpeng Sheng), the National Key Research and Development Program (grant 2019YFC1316000 to Tingbo Liang), the National Natural Science Foundation of China (grant 81871925 to Xueli Bai), the National Key Research and Development Program of China (grant 2020YFA0804300 to Qi Zhang) and the National Natural Science Foundation of China (grant U20A20378 to Tingbo Liang).
Competing interests None declared.
Provenance and peer review Not commissioned; externally peer reviewed.
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