The department of Medical Genetics, Naval Medical University, Shanghai, 200433, China.
The Third Department of Hepatic Surgery, Eastern Hepatobiliary Surgery Hospital Affiliated to Naval Medical University, Shanghai, 200438, China.
Theranostics. 2022 May 16;12(9):4163-4180. doi: 10.7150/thno.71873. eCollection 2022.
Hepatocellular carcinoma (HCC) is a highly heterogeneous and malignant disease with the complex immune microenvironment, which ultimately influence clinic outcomes of patients. However, the spatial expression patterns of diverse immune cells among tumor microenvironment remain to be further deciphered. Spatial transcriptomics sequencing (ST) was implemented on two portions of HCC specimens. Differentially expressed genes, cell cycle phases, epithelial-mesenchymal features, pseudo-time and immune infiltration analysis were applied to demonstrate the intratumor heterogeneity and define the specific immune-related regions, and the results were further validated by a second analysis on another ST study. and experiments were conducted to confirm the functional mechanisms of key molecules such as CCL15, CCL19 and CCL21. Clinical tissue samples were used to assess their potential prognostic and therapeutic values. Totally, 7553 spots were categorized into 15 subsets by hierarchical clustering, and malignant subsets with intratumor heterogeneity phenotypes were identified. Spatial heterogeneity from distinct sectors highlights specific chemokines: CCL15 is remarkable in the core region of the carcinoma sector and facilitates the immunosuppressive microenvironment by recruiting and polarizing M2-like macrophages and ; High expression of CCL15 and CD163 respectively predicts poor prognosis of HCC patients, and the combined application of them has better predictive value. CCL19 and CCL21, sharing similar spatial expression patterns, are highly-correlated and prominent in the immune infiltration enrichment and recruit CD3 T cells and CD20 B cells to inhibit the growth of HCC, indicating a good prognosis of HCC patients. Taken together, our studies preliminarily reveal intratumor heterogeneity of HCC based on ST techniques and unravel the previously unexplored spatial expression patterns in the immune microenvironment. We also highlight the clinical significance and spatial discrepancy of key molecules, providing novel insight for further developing therapeutic strategies in HCC.
肝细胞癌 (HCC) 是一种高度异质性和恶性疾病，具有复杂的免疫微环境，最终影响患者的临床结局。然而，肿瘤微环境中不同免疫细胞的空间表达模式仍有待进一步阐明。对 HCC 标本的两部分进行了空间转录组测序 (ST)。应用差异表达基因、细胞周期阶段、上皮-间充质特征、伪时间和免疫浸润分析来展示肿瘤内异质性，并定义特定的免疫相关区域，结果通过对另一项 ST 研究的第二次分析进一步验证。进行了 和 实验以确认关键分子（如 CCL15、CCL19 和 CCL21）的功能机制。使用临床组织样本评估它们的潜在预后和治疗价值。通过层次聚类将 7553 个斑点分为 15 个子集，并鉴定出具有肿瘤内异质性表型的恶性子集。来自不同区域的空间异质性突出了特定的趋化因子：CCL15 在癌区核心区域显著，通过招募和极化 M2 样巨噬细胞 和 来促进免疫抑制微环境；CCL15 和 CD163 的高表达分别预示着 HCC 患者预后不良，两者联合应用具有更好的预测价值。CCL19 和 CCL21 具有相似的空间表达模式，高度相关，在免疫浸润富集中突出，并招募 CD3 T 细胞和 CD20 B 细胞抑制 HCC 生长，预示着 HCC 患者的良好预后。总之，我们的研究初步基于 ST 技术揭示了 HCC 的肿瘤内异质性，并揭示了免疫微环境中以前未被探索的空间表达模式。我们还强调了关键分子的临床意义和空间差异，为进一步开发 HCC 的治疗策略提供了新的见解。
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