Yang Yongheng, Ni Qingqiang, Li Hongguang, Sun Jiuzheng, Zhou Xia, Qu Lingxin, Wang Liyuan, Zhao Chuanzong, Zhang Xiaolu
Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China.
Department of Hepatobiliary Surgery, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, China.
Hepatology. 2024 Dec 12;82(3):582-98. doi: 10.1097/HEP.0000000000001191.
Ambiguous understanding of tumors and tumor microenvironments (TMEs) hinders accurate diagnosis and available treatment for multifocal hepatocellular carcinoma (HCC) covering intrahepatic metastasis (IM) and multicentric occurrence (MO). Here, we characterized the diverse TMEs of IM and MO identified by whole-exome sequencing at single-cell resolution.
We performed parallel whole-exome sequencing and scRNA-seq on 23 samples from 7 patients to profile their TMEs when major results were validated by immunohistochemistry in the additional cohort. Integrative analysis of whole-exome sequencing and single-cell RNA sequencing found that malignant cells in IM showed higher intratumor heterogeneity, stemness, and more activated metabolism than those in MO. Tumors from IM shared similar TMEs while distinct TMEs were noticed in those from MO. Furthermore, CD20+ B cells, plasma cells, and conventional type II dendritic cells (cDC2s) were decreased in IM relative to MO while T cells in IM exhibited a more terminally exhausted capacity with a higher proportion of proliferative/exhausted T cells than that in MO. Both CD20 and CD1C correlated with better prognosis in multifocal HCC. Additionally, MMP9+ tumor-associated macrophages were enriched across IM and MO, which formed cellular niches with regulatory T cells and proliferative/exhausted T cells.
Our findings deeply decipher the heterogeneous TMEs between IM and MO, which provide a comprehensive landscape of multifocal HCC.
对肿瘤及肿瘤微环境（TME）的模糊认识阻碍了对涵盖肝内转移（IM）和多中心发生（MO）的多灶性肝细胞癌（HCC）的准确诊断和有效治疗。在此，我们以单细胞分辨率对通过全外显子测序鉴定出的IM和MO的不同TME进行了特征分析。
我们对7例患者的23个样本进行了平行全外显子测序和scRNA-seq，以分析其TME，同时在另外一组队列中通过免疫组化验证主要结果。全外显子测序和单细胞RNA测序的综合分析发现，IM中的恶性细胞比MO中的恶性细胞表现出更高的肿瘤内异质性、干性和更活跃的代谢。IM来源的肿瘤具有相似的TME，而MO来源的肿瘤则具有不同的TME。此外，相对于MO，IM中的CD20+B细胞、浆细胞和传统II型树突状细胞（cDC2）减少，而IM中的T细胞表现出更终末耗竭的能力，增殖/耗竭T细胞的比例高于MO。CD20和CD1C均与多灶性HCC的较好预后相关。此外，MMP9+肿瘤相关巨噬细胞在IM和MO中均富集，它们与调节性T细胞和增殖/耗竭T细胞形成细胞龛。
我们的研究结果深入解析了IM和MO之间异质性的TME，为多灶性HCC提供了全面的图景。
