Abstract

Clonal evolution of a tumor ecosystem depends on different selection pressures that are principally immune and treatment mediated. We integrate RNA-seq, DNA sequencing, TCR-seq and SNP array data across multiple regions of liver cancer specimens to map spatio-temporal interactions between cancer and immune cells. We investigate how these interactions reflect intra-tumor heterogeneity (ITH) by correlating regional neo-epitope and viral antigen burden with the regional adaptive immune response. Regional expression of passenger mutations dominantly recruits adaptive responses as opposed to hepatitis B virus and cancer-testis antigens. We detect different clonal expansion of the adaptive immune system in distant regions of the same tumor. An ITH-based gene signature improves single-biopsy patient survival predictions and an expression survey of 38,553 single cells across 7 regions of 2 patients further reveals heterogeneity in liver cancer. These data quantify transcriptomic ITH and how the different components of the HCC ecosystem interact during cancer evolution.

Immune-mediated selection pressures impact the clonal evolution of tumours. Here, in hepatocellular carcinoma the authors map spatio-temporal interactions between tumor and immune cells, highlighting the regulatory substrate of intra-tumoural heterogeneity that correlates with regional adaptive immune responses.

Details

Title
Intratumoral heterogeneity and clonal evolution in liver cancer
Author
Losic Bojan 1 ; Craig, Amanda J 2 ; Villacorta-Martin, Carlos 2 ; Martins-Filho, Sebastiao N 3 ; Akers, Nicholas 4 ; Chen, Xintong 5 ; Ahsen, Mehmet E 5   VIAFID ORCID Logo  ; von Felden Johann 6   VIAFID ORCID Logo  ; Ismail, Labgaa 7   VIAFID ORCID Logo  ; DʹAvola Delia 8 ; Kimaada, Allette 9 ; Lira, Sergio A 10 ; Furtado, Glaucia C 10 ; Garcia-Lezana, Teresa 2   VIAFID ORCID Logo  ; Restrepo, Paula 5 ; Stueck Ashley 11 ; Ward, Stephen C 12 ; Fiel, Maria I 12 ; Hiotis, Spiros P 13 ; Gunasekaran Ganesh 13 ; Sia, Daniela 2 ; Schadt, Eric E 14   VIAFID ORCID Logo  ; Sebra, Robert 15 ; Schwartz, Myron 13   VIAFID ORCID Logo  ; Llovet, Josep M 16   VIAFID ORCID Logo  ; Swan, Thung 12 ; Stolovitzky Gustavo 17 ; Villanueva Augusto 18   VIAFID ORCID Logo 

1  Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, Department of Genetics and Genomic Sciences, Cancer Immunology Program, New York, USA (GRID:grid.59734.3c) (ISNI:0000 0001 0670 2351) ; Icahn School of Medicine at Mount Sinai, Icahn Institute for Data Science and Genomic Technology, New York, USA (GRID:grid.59734.3c) (ISNI:0000 0001 0670 2351) ; Icahn School of Medicine at Mount Sinai, Diabetes, Obesity and Metabolism Institute, New York, USA (GRID:grid.59734.3c) (ISNI:0000 0001 0670 2351) 
2  Icahn School of Medicine at Mount Sinai, Division of Liver Diseases, Department of Medicine, Liver Cancer Program, Tisch Cancer Institute, Graduate School of Biomedical Sciences, New York, USA (GRID:grid.59734.3c) (ISNI:0000 0001 0670 2351) 
3  Icahn School of Medicine at Mount Sinai, Division of Liver Diseases, Department of Medicine, Liver Cancer Program, Tisch Cancer Institute, Graduate School of Biomedical Sciences, New York, USA (GRID:grid.59734.3c) (ISNI:0000 0001 0670 2351) ; University of Sao Paulo School of Medicine, Department of Pathology, Sao Paulo, Brazil (GRID:grid.11899.38) (ISNI:0000 0004 1937 0722) 
4  Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, Department of Genetics and Genomic Sciences, Cancer Immunology Program, New York, USA (GRID:grid.59734.3c) (ISNI:0000 0001 0670 2351) ; Adaptive Biotechnologies, Seattle, USA (GRID:grid.421940.a) 
5  Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, Department of Genetics and Genomic Sciences, Cancer Immunology Program, New York, USA (GRID:grid.59734.3c) (ISNI:0000 0001 0670 2351) 
6  Icahn School of Medicine at Mount Sinai, Division of Liver Diseases, Department of Medicine, Liver Cancer Program, Tisch Cancer Institute, Graduate School of Biomedical Sciences, New York, USA (GRID:grid.59734.3c) (ISNI:0000 0001 0670 2351) ; University Medical Center Hamburg-Eppendorf, I. Department of Medicine, Hamburg, Germany (GRID:grid.13648.38) (ISNI:0000 0001 2180 3484) 
7  Icahn School of Medicine at Mount Sinai, Division of Liver Diseases, Department of Medicine, Liver Cancer Program, Tisch Cancer Institute, Graduate School of Biomedical Sciences, New York, USA (GRID:grid.59734.3c) (ISNI:0000 0001 0670 2351) ; Lausanne University Hospital CHUV, Department of Visceral Surgery, Lausanne, Switzerland (GRID:grid.8515.9) (ISNI:0000 0001 0423 4662) 
8  Icahn School of Medicine at Mount Sinai, Division of Liver Diseases, Department of Medicine, Liver Cancer Program, Tisch Cancer Institute, Graduate School of Biomedical Sciences, New York, USA (GRID:grid.59734.3c) (ISNI:0000 0001 0670 2351) ; Clínica Universidad de Navarra, Liver Unit and Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Pamplona, Spain (GRID:grid.411730.0) (ISNI:0000 0001 2191 685X) 
9  Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, Department of Genetics and Genomic Sciences, Cancer Immunology Program, New York, USA (GRID:grid.59734.3c) (ISNI:0000 0001 0670 2351) ; Icahn School of Medicine at Mount Sinai, Icahn Institute for Data Science and Genomic Technology, New York, USA (GRID:grid.59734.3c) (ISNI:0000 0001 0670 2351) 
10  Icahn School of Medicine at Mount Sinai, Immunology Institute, New York, USA (GRID:grid.59734.3c) (ISNI:0000 0001 0670 2351) 
11  Dalhousie University, Department of Pathology, Halifax, Canada (GRID:grid.55602.34) (ISNI:0000 0004 1936 8200) 
12  Icahn School of Medicine at Mount Sinai, Department of Pathology, New York, USA (GRID:grid.59734.3c) (ISNI:0000 0001 0670 2351) 
13  Icahn School of Medicine at Mount Sinai, Department of Surgery, New York, USA (GRID:grid.59734.3c) (ISNI:0000 0001 0670 2351) 
14  Icahn School of Medicine at Mount Sinai, Icahn Institute for Data Science and Genomic Technology, New York, USA (GRID:grid.59734.3c) (ISNI:0000 0001 0670 2351) ; Sema4, a Mount Sinai venture, Stamford, USA (GRID:grid.59734.3c) 
15  Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, Department of Genetics and Genomic Sciences, Cancer Immunology Program, New York, USA (GRID:grid.59734.3c) (ISNI:0000 0001 0670 2351) ; Icahn School of Medicine at Mount Sinai, Icahn Institute for Data Science and Genomic Technology, New York, USA (GRID:grid.59734.3c) (ISNI:0000 0001 0670 2351) ; Sema4, a Mount Sinai venture, Stamford, USA (GRID:grid.59734.3c) 
16  Icahn School of Medicine at Mount Sinai, Division of Liver Diseases, Department of Medicine, Liver Cancer Program, Tisch Cancer Institute, Graduate School of Biomedical Sciences, New York, USA (GRID:grid.59734.3c) (ISNI:0000 0001 0670 2351) ; Hospital Clinic, Universitat de Barcelona, Liver Cancer Translational Research Laboratory, BCLC Group, IDIBAPS, Barcelona, Spain (GRID:grid.410458.c) (ISNI:0000 0000 9635 9413) ; Institució Catalana de Recerca i Estudis Avançats, Barcelona, Spain (GRID:grid.425902.8) (ISNI:0000 0000 9601 989X) 
17  Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, Department of Genetics and Genomic Sciences, Cancer Immunology Program, New York, USA (GRID:grid.59734.3c) (ISNI:0000 0001 0670 2351) ; IBM T. J. Watson Research Center, Yorktown Heights, New York, USA (GRID:grid.481554.9) 
18  Icahn School of Medicine at Mount Sinai, Division of Liver Diseases, Department of Medicine, Liver Cancer Program, Tisch Cancer Institute, Graduate School of Biomedical Sciences, New York, USA (GRID:grid.59734.3c) (ISNI:0000 0001 0670 2351) ; Icahn School of Medicine at Mount Sinai, Division of Hematology and Medical Oncology, Department of Medicine, New York, USA (GRID:grid.59734.3c) (ISNI:0000 0001 0670 2351) 
Publication year
2020
Publication date
2020
Publisher
Nature Publishing Group
e-ISSN
20411723
Source type
Scholarly Journal
Language of publication
English
DOI
https://doi.org/10.1038/s41467-019-14050-z
ProQuest document ID
2342441729
Copyright
This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.