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. 2025 May 1;81(5):1452-1467.
doi: 10.1097/HEP.0000000000000979. Epub 2024 Jun 20.

Spatial proteomic landscape of primary and relapsed hepatocellular carcinoma reveals immune escape characteristics in early relapse

Meilin Yang  1   2   3 , Xiaoyi Song  2   3 , Fan Zhang  4 , Mingan Li  5 , Wuguang Chang  1   2   3 , Zheyan Wang  2   3 , Man Li  2   3   6   7 , Hong Shan  2   3   8 , Dan Li  1   2   3
Affiliations

Spatial proteomic landscape of primary and relapsed hepatocellular carcinoma reveals immune escape characteristics in early relapse

Meilin Yang et al. Hepatology. .

Abstract

Background and aims: Surgical resection serves as the principal curative strategy for HCC, yet the incidence of postoperative recurrence remains alarmingly high. However, the spatial molecular structural alterations contributing to postoperative recurrence in HCC are still poorly understood.

Approach and results: We employed imaging mass cytometry to profile the in situ expression of 33 proteins within 358,729 single cells of 92 clinically annotated surgical specimens from 46 patients who were treated with surgical resections for primary and relapsed tumors. We revealed the recurrence progression of HCC was governed by the dynamic spatial distribution and functional interplay of diverse cell types across adjacent normal, tumor margin, and intratumor regions. Our exhaustive analyses revealed an aggressive, immunosuppression-related spatial ecosystem in relapsed HCC. Additionally, we illustrated the prominent implications of the tumor microenvironment of tumor margins in association with relapse HCC. Moreover, we identified a novel subpopulation of dendritic cells (PDL1 + CD103 + DCs) enriched in the peritumoral area that correlated with early postoperative recurrence, which was further validated in an external cohort. Through the analysis of single-cell RNA sequencing data, we found the interaction of PDL1 + CD103 + DCs with regulatory T cells and exhausted T cells enhanced immunosuppression and immune escape through multiple ligand-receptor pathways.

Conclusions: We comprehensively depicted the spatial landscape of single-cell dynamics and multicellular architecture within primary and relapsed HCC. Our findings highlight spatial organization as a prominent determinant of HCC recurrence and provide valuable insight into the immune evasion mechanisms driving recurrence.

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