Intratumoural immune heterogeneity as a hallmark of tumour evolution and progression in hepatocellular carcinoma

Phuong H. D. Nguyen, Siming Ma, Cheryl Z. J. Phua, Neslihan A. Kaya, Hannah L. H. Lai, Chun Jye Lim, Jia Qi Lim, Martin Wasser, Liyun Lai, Wai Leong Tam, Tony K. H. Lim, Wei Keat Wan, Tracy Loh, Wei Qiang Leow, Yin Huei Pang, Chung Yip Chan, Ser Yee Lee, Peng Chung Cheow, Han Chong Toh, Florent Ginhoux, Shridhar Iyer, Alfred W. C. Kow, Yock Young Dan, Alexander Chung, Glen K. Bonney, Brian K. P. Goh, Salvatore Albani, Pierce K. H. Chow (), Weiwei Zhai () and Valerie Chew ()
Additional contact information
Phuong H. D. Nguyen: Translational Immunology Institute (TII), SingHealth-DukeNUS Academic Medical Centre
Siming Ma: Genome Institute of Singapore (GIS), Agency for Science, Technology and Research (A*STAR)
Cheryl Z. J. Phua: Genome Institute of Singapore (GIS), Agency for Science, Technology and Research (A*STAR)
Neslihan A. Kaya: Genome Institute of Singapore (GIS), Agency for Science, Technology and Research (A*STAR)
Hannah L. H. Lai: Genome Institute of Singapore (GIS), Agency for Science, Technology and Research (A*STAR)
Chun Jye Lim: Translational Immunology Institute (TII), SingHealth-DukeNUS Academic Medical Centre
Jia Qi Lim: Genome Institute of Singapore (GIS), Agency for Science, Technology and Research (A*STAR)
Martin Wasser: Translational Immunology Institute (TII), SingHealth-DukeNUS Academic Medical Centre
Liyun Lai: Translational Immunology Institute (TII), SingHealth-DukeNUS Academic Medical Centre
Wai Leong Tam: Genome Institute of Singapore (GIS), Agency for Science, Technology and Research (A*STAR)
Tony K. H. Lim: Singapore General Hospital
Wei Keat Wan: Singapore General Hospital
Tracy Loh: Singapore General Hospital
Wei Qiang Leow: Singapore General Hospital
Yin Huei Pang: National University Hospital Singapore
Chung Yip Chan: Duke-NUS Medical School
Ser Yee Lee: Duke-NUS Medical School
Peng Chung Cheow: Duke-NUS Medical School
Han Chong Toh: Duke-NUS Medical School
Florent Ginhoux: Translational Immunology Institute (TII), SingHealth-DukeNUS Academic Medical Centre
Shridhar Iyer: University Surgical Cluster, National University Health System
Alfred W. C. Kow: University Surgical Cluster, National University Health System
Yock Young Dan: National University Hospital Singapore
Alexander Chung: Duke-NUS Medical School
Glen K. Bonney: University Surgical Cluster, National University Health System
Brian K. P. Goh: Duke-NUS Medical School
Salvatore Albani: Translational Immunology Institute (TII), SingHealth-DukeNUS Academic Medical Centre
Pierce K. H. Chow: Duke-NUS Medical School
Weiwei Zhai: Genome Institute of Singapore (GIS), Agency for Science, Technology and Research (A*STAR)
Valerie Chew: Translational Immunology Institute (TII), SingHealth-DukeNUS Academic Medical Centre

Nature Communications, 2021, vol. 12, issue 1, 1-13

Abstract: Abstract The clinical relevance of immune landscape intratumoural heterogeneity (immune-ITH) and its role in tumour evolution remain largely unexplored. Here, we uncover significant spatial and phenotypic immune-ITH from multiple tumour sectors and decipher its relationship with tumour evolution and disease progression in hepatocellular carcinomas (HCC). Immune-ITH is associated with tumour transcriptomic-ITH, mutational burden and distinct immune microenvironments. Tumours with low immune-ITH experience higher immunoselective pressure and escape via loss of heterozygosity in human leukocyte antigens and immunoediting. Instead, the tumours with high immune-ITH evolve to a more immunosuppressive/exhausted microenvironment. This gradient of immune pressure along with immune-ITH represents a hallmark of tumour evolution, which is closely linked to the transcriptome-immune networks contributing to disease progression and immune inactivation. Remarkably, high immune-ITH and its transcriptomic signature are predictive for worse clinical outcome in HCC patients. This in-depth investigation of ITH provides evidence on tumour-immune co-evolution along HCC progression.

Date: 2021
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DOI: 10.1038/s41467-020-20171-7

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