Landscape and Dynamics of Single Immune Cells in Hepatocellular Carcinoma

Qiming Zhang; Yao He; Nan Luo; Shashank J Patel; Yanjie Han; Ranran Gao; Madhura Modak; Sebastian Carotta; Christian Haslinger; David Kind; Gregory W Peet; Guojie Zhong; Shuangjia Lu; Weihua Zhu; Yilei Mao; Mengmeng Xiao; Michael Bergmann; Xueda Hu; Sid P Kerkar; Anne B Vogt; Stefan Pflanz; Kang Liu; Jirun Peng; Xianwen Ren; Zemin Zhang

doi:10.1016/j.cell.2019.10.003

Landscape and Dynamics of Single Immune Cells in Hepatocellular Carcinoma

Cell. 2019 Oct 31;179(4):829-845.e20. doi: 10.1016/j.cell.2019.10.003.

Authors

Qiming Zhang¹, Yao He², Nan Luo³, Shashank J Patel⁴, Yanjie Han¹, Ranran Gao¹, Madhura Modak⁵, Sebastian Carotta⁶, Christian Haslinger⁷, David Kind⁷, Gregory W Peet⁴, Guojie Zhong¹, Shuangjia Lu¹, Weihua Zhu⁸, Yilei Mao⁹, Mengmeng Xiao¹⁰, Michael Bergmann¹¹, Xueda Hu¹, Sid P Kerkar⁴, Anne B Vogt¹², Stefan Pflanz⁵, Kang Liu¹³, Jirun Peng¹⁴, Xianwen Ren¹⁵, Zemin Zhang¹⁶

Affiliations

¹ BIOPIC, Beijing Advanced Innovation Center for Genomics, School of Life Sciences, Peking University, Beijing 100871, China.
² Peking-Tsinghua Center for Life Sciences, Academy for Advanced Interdisciplinary Studies, Peking University, Beijing 100871, China.
³ Department of Surgery, Beijing Shijitan Hospital, Capital Medical University, Beijing 100038, China; Ninth School of Clinical Medicine, Peking University, Beijing 100038, China.
⁴ Department of Cancer Immunology and Immune Modulation, Boehringer Ingelheim Pharmaceuticals, Inc., 900 Ridgebury Road, Ridgefield, CT 06877, USA.
⁵ Department of Cancer Immunology and Immune Modulation, Boehringer Ingelheim Pharma, Birkendorfer Str. 65, 88400 Biberach, Germany.
⁶ Department of Cancer Cell Signaling, Boehringer Ingelheim RCV GmBH & Co KG., Dr. Boehringer Gasse 5-11, 1120 Vienna, Austria.
⁷ Department of Computational Biology and Genomics, Boehringer Ingelheim Pharma, Birkendorfer Str. 65, 88400 Biberach, Germany.
⁸ Department of Hepatobiliary Surgery, Peking University People's Hospital, Beijing 100044, China.
⁹ Department of Liver Surgery, Peking Union Medical College Hospital, Beijing 100730, China.
¹⁰ Department of Retroperitoneal Tumor Surgery, Peking University International Hospital, Beijing 102206, China.
¹¹ Department of Surgery and Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria.
¹² Department of Human Cancer Immunology, Boehringer Ingelheim RCV GmBH & Co KG., Dr. Boehringer Gasse 5-11, 1120 Vienna, Austria.
¹³ Department of Cancer Immunology and Immune Modulation, Boehringer Ingelheim Pharmaceuticals, Inc., 900 Ridgebury Road, Ridgefield, CT 06877, USA. Electronic address: kang_3.liu@boehringer-ingelheim.com.
¹⁴ Department of Surgery, Beijing Shijitan Hospital, Capital Medical University, Beijing 100038, China; Ninth School of Clinical Medicine, Peking University, Beijing 100038, China. Electronic address: pengjr@medmail.com.cn.
¹⁵ BIOPIC, Beijing Advanced Innovation Center for Genomics, School of Life Sciences, Peking University, Beijing 100871, China. Electronic address: renxwise@pku.edu.cn.
¹⁶ BIOPIC, Beijing Advanced Innovation Center for Genomics, School of Life Sciences, Peking University, Beijing 100871, China; Peking-Tsinghua Center for Life Sciences, Academy for Advanced Interdisciplinary Studies, Peking University, Beijing 100871, China. Electronic address: zemin@pku.edu.cn.

PMID: 31675496
DOI: 10.1016/j.cell.2019.10.003

Abstract

The immune microenvironment of hepatocellular carcinoma (HCC) is poorly characterized. Combining two single-cell RNA sequencing technologies, we produced transcriptomes of CD45⁺ immune cells for HCC patients from five immune-relevant sites: tumor, adjacent liver, hepatic lymph node (LN), blood, and ascites. A cluster of LAMP3⁺ dendritic cells (DCs) appeared to be the mature form of conventional DCs and possessed the potential to migrate from tumors to LNs. LAMP3⁺ DCs also expressed diverse immune-relevant ligands and exhibited potential to regulate multiple subtypes of lymphocytes. Of the macrophages in tumors that exhibited distinct transcriptional states, tumor-associated macrophages (TAMs) were associated with poor prognosis, and we established the inflammatory role of SLC40A1 and GPNMB in these cells. Further, myeloid and lymphoid cells in ascites were predominantly linked to tumor and blood origins, respectively. The dynamic properties of diverse CD45⁺ cell types revealed by this study add new dimensions to the immune landscape of HCC.

MeSH terms

Carcinoma, Hepatocellular / genetics
Carcinoma, Hepatocellular / immunology*
Carcinoma, Hepatocellular / pathology
Cation Transport Proteins / genetics*
Cell Communication / genetics
Cell Communication / immunology
Cell Lineage / genetics
Cell Lineage / immunology
Dendritic Cells / immunology
Dendritic Cells / pathology
Gene Expression Regulation, Neoplastic
Humans
Inflammation / genetics
Inflammation / immunology*
Inflammation / pathology
Leukocyte Common Antigens / immunology
Liver / immunology
Liver / pathology
Liver Neoplasms / genetics
Liver Neoplasms / immunology*
Liver Neoplasms / pathology
Lymph Nodes / immunology
Lymph Nodes / pathology
Lymphocytes / immunology
Lymphocytes / pathology
Lysosomal Membrane Proteins / genetics
Macrophages / immunology
Macrophages / pathology
Membrane Glycoproteins / genetics*
Myeloid Cells / immunology
Myeloid Cells / pathology
Neoplasm Proteins / genetics
Sequence Analysis, RNA
Single-Cell Analysis
Transcriptome / genetics
Transcriptome / immunology
Tumor Microenvironment / genetics
Tumor Microenvironment / immunology

Substances

Cation Transport Proteins
GPNMB protein, human
LAMP3 protein, human
Lysosomal Membrane Proteins
Membrane Glycoproteins
Neoplasm Proteins
metal transporting protein 1
Leukocyte Common Antigens