作者
Yun‐Fan Sun,Pin Wu,Zefan Zhang,Zejian Wang,Kaiyu Zhou,Mei Song,Yuan Ji,Fenglin Zang,Lifeng Lou,Keqiang Rao,Pengxiang Wang,Yutong Gu,Jianxin Gu,Binfeng Lu,Limeng Chen,Xiuqi Pan,Xin Zhao,Lihua Peng,Dongbing Liu,Xun Chen,Kui Wang,Penghui Lin,Liang Wu,Yu‐Lin Su,Min Du,Rongkui Luo,Xin‐Rong Yang,Shuang‐Jian Qiu,Ying‐Hong Shi,Hui–Chuan Sun,Ji Zhou,Xingxu Huang,David H. Peng,Liye Zhang,Jia Fan
摘要
Summary
Comprehensive molecular analyses of metastatic hepatocellular carcinoma (HCC) are lacking. Here, we generate multi-omic profiling of 257 primary and 176 metastatic regions from 182 HCC patients. Primary tumors rich in hypoxia signatures facilitated polyclonal dissemination. Genomic divergence between primary and metastatic HCC is high, and early dissemination is prevalent. The remarkable neoantigen intratumor heterogeneity observed in metastases is associated with decreased T cell reactivity, resulting from disruptions to neoantigen presentation. We identify somatic copy number alterations as highly selected events driving metastasis. Subclones without Wnt mutations show a stronger selective advantage for metastasis than those with Wnt mutations and are characterized by a microenvironment rich in activated fibroblasts favoring a pro-metastatic phenotype. Finally, metastases without Wnt mutations exhibit higher enrichment of immunosuppressive B cells that mediate terminal exhaustion of CD8+ T cells via HLA-E:CD94-NKG2A checkpoint axis. Collectively, our results provide a multi-dimensional dissection of the complex evolutionary process of metastasis.