Background & Aims: Surgical resection serves as the principal curative strategy for hepatocellular carcinoma (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 & 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 TME 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 scRNA-seq data, we found the interaction of PDL1+CD103+ DCs with regulatory T cells and exhausted T cells enhanced immunosuppression and immune escape via 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 is a prominent determinant of HCC recurrence and provide a valuable insight into the immune evasion mechanisms driving recurrence.

中文翻译：

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原发性和复发性肝细胞癌的空间蛋白质组景观揭示了早期复发的免疫逃逸特征


背景与目的：手术切除是肝细胞癌（HCC）的主要治疗策略，但术后复发率仍然高得惊人。然而，导致 HCC 术后复发的空间分子结构改变仍知之甚少。方法和结果：我们采用成像质谱流式细胞仪对来自 46 名接受原发性和复发性肿瘤手术切除的患者的 92 份临床注释手术标本的 358,729 个单细胞内 33 种蛋白质的原位表达进行了分析。我们揭示了 HCC 的复发进展受相邻正常区域、肿瘤边缘和肿瘤内区域不同细胞类型的动态空间分布和功能相互作用的控制。我们详尽的分析揭示了复发性 HCC 中存在一个侵袭性的、与免疫抑制相关的空间生态系统。此外，我们还说明了肿瘤边缘 TME 与复发性 HCC 相关的显着影响。此外，我们还发现了一种新的树突状细胞亚群（PDL1+CD103+ DC），其富集于瘤周区域，与术后早期复发相关，这在外部队列中得到了进一步验证。通过scRNA-seq数据分析，我们发现PDL1+CD103+ DC与调节性T细胞和耗竭T细胞的相互作用通过多种配体-受体途径增强免疫抑制和免疫逃逸。结论：我们全面描述了原发性和复发性 HCC 中单细胞动力学和多细胞结构的空间景观。我们的研究结果强调空间组织是 HCC 复发的一个重要决定因素，并为驱动复发的免疫逃避机制提供了宝贵的见解。