Heterogeneous immunogenomic features and distinct escape mechanisms in multifocal hepatocellular carcinoma,Journal of Hepatology

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Heterogeneous immunogenomic features and distinct escape mechanisms in multifocal hepatocellular carcinoma
Journal of Hepatology ( IF 26.8 ) Pub Date : 2020-05-01 , DOI: 10.1016/j.jhep.2019.12.014
Liang-Qing Dong ₁ , Li-Hua Peng ₂ , Li-Jie Ma ₁ , Dong-Bing Liu ₃ , Shu Zhang ₁ , Shu-Zhen Luo ₂ , Jun-Hua Rao ₂ , Hong-Wen Zhu ₄ , Shuai-Xi Yang ₁ , Shui-Jun Xi ₁ , Min Chen ₅ , Fan-Fan Xie ₂ , Fu-Qiang Li ₂ , Wen-Hui Li ₂ , Chen Ye ₂ , Li-Ya Lin ₂ , Yu-Jue Wang ₂ , Xiao-Ying Wang ₁ , Da-Ming Gao ₅ , Hu Zhou ₄ , Huan-Ming Yang ₆ , Jian Wang ₆ , Shi-da Zhu ₇ , Xiang-Dong Wang ₈ , Ya Cao ₉ , Jian Zhou ₁₀ , Jia Fan ₁₁ , Kui Wu ₁₂ , Qiang Gao ₁₀

Affiliation

Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, and Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education), Fudan University, Shanghai 200032, China.
BGI-Shenzhen, Shenzhen 518083, China.
BGI-Shenzhen, Shenzhen 518083, China; Guangdong Provincial Key Laboratory of Human Disease Genomics, Shenzhen Key Laboratory of Genomics, BGI-Shenzhen, Shenzhen 518083, China.
Department of Analytical Chemistry and CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, China.
CAS Key Laboratory of Systems Biology, Innovation Center for Cell Signaling Network, CAS enter for Excellence in Molecular Cell Science, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China.
BGI-Shenzhen, Shenzhen 518083, China; James D. Watson Institute of Genome Sciences, Hangzhou 310058, China.
BGI-Shenzhen, Shenzhen 518083, China; Department of Biology, University of Copenhagen, Copenhagen N DK-2200, Denmark.
Shanghai Institute of Clinical Bioinformatics, Zhongshan Hospital, Fudan University, Shanghai 200032, China.
Key Laboratory of Carcinogenesis and Invasion, Chinese Ministry of Education, Xiangya Hospital, Central South University, Changsha 410078, China.
Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, and Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education), Fudan University, Shanghai 200032, China; Key Laboratory of Medical Epigenetics and Metabolism, Institutes of Biomedical Sciences, Fudan University, Shanghai 200032, China.
Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, and Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education), Fudan University, Shanghai 200032, China; Key Laboratory of Medical Epigenetics and Metabolism, Institutes of Biomedical Sciences, Fudan University, Shanghai 200032, China; State Key Laboratory of Genetic Engineering, Fudan University, Shanghai 200433, China.
BGI-Shenzhen, Shenzhen 518083, China; Guangdong Provincial Key Laboratory of Human Disease Genomics, Shenzhen Key Laboratory of Genomics, BGI-Shenzhen, Shenzhen 518083, China; Department of Biology, University of Copenhagen, Copenhagen N DK-2200, Denmark.

BACKGROUND AIMS Multifocal tumors, developed either from intrahepatic metastasis (IM) or multicentric occurrence (MO), is a distinct feature of hepatocellular carcinoma (HCC). Immunogenomic characterization of multifocal HCC is important for understanding immune escape in different lesions and developing immunotherapy. METHODS We combined whole exome/transcriptome sequencing, multiplex immunostaining, immunopeptidomes, T-cell receptor (TCR) sequencing and bioinformatic analyses of 47 tumors from 15 HCC patients with multifocal lesions. RESULTS IM and MO demonstrated distinct clonal architecture, mutational spectrum and genetic susceptibility. The immune microenvironment also displayed spatiotemporal heterogeneity, such as less T cell and more M2 macrophage infiltration in IM and higher expression of inhibitory immune checkpoints in MO. Similar to mutational profiles, shared neoantigens and TCR repertoires among tumors from the same patients were abundant in IM but scarce in MO. Combining neoantigen prediction and immunopeptidomes identified T-cell specific neoepitopes and achieved a high verification rate in vitro. Immunoediting mainly occurred in MO but not IM, due to the relatively low immune infiltration. HLA LOH, identified in 17% of multifocal HCC, hampered the ability of MHC to present neoantigens, especially in IM. An integrated analysis of Immunoscore, Immunoediting, TCR clonality and HLA LOH of each tumor could stratify patients into two groups with high or low risk of recurrence (P=0.038). CONCLUSION Our study comprehensively characterized the genetic structure, neoepitope landscape, T cell profile and immunoediting status that collectively shape tumor evolution, which may optimize personalized immunotherapies for multifocal HCC.

中文翻译：

多灶性肝细胞癌的异质免疫基因组特征和不同的逃逸机制

背景目的多灶性肿瘤由肝内转移 (IM) 或多中心发生 (MO) 发展而来，是肝细胞癌 (HCC) 的一个明显特征。多灶性 HCC 的免疫基因组学特征对于了解不同病变中的免疫逃逸和开发免疫疗法很重要。方法我们结合了全外显子组/转录组测序、多重免疫染色、免疫肽组、T 细胞受体 (TCR) 测序和生物信息学分析，对来自 15 名具有多灶性病变的 HCC 患者的 47 个肿瘤进行了分析。结果 IM 和 MO 表现出不同的克隆结构、突变谱和遗传易感性。免疫微环境也表现出时空异质性，例如 IM 中较少的 T 细胞和更多的 M2 巨噬细胞浸润以及 MO 中抑制性免疫检查点的更高表达。与突变谱相似，来自同一患者的肿瘤之间共享的新抗原和 TCR 库在 IM 中很丰富，但在 MO 中很少。结合新抗原预测和免疫肽组鉴定了 T 细胞特异性新表位，并在体外实现了高验证率。由于免疫浸润相对较低，免疫编辑主要发生在 MO 而不是 IM。在 17% 的多灶性 HCC 中鉴定出 HLA LOH，阻碍了 MHC 呈递新抗原的能力，尤其是在 IM 中。对每个肿瘤的免疫评分、免疫编辑、TCR 克隆性和 HLA LOH 的综合分析可以将患者分为复发风险高或低的两组（P = 0.038）。结论我们的研究全面表征了共同塑造肿瘤进化的遗传结构、新表位景观、T 细胞谱和免疫编辑状态，

更新日期：2020-05-01

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