Intratumoural immune heterogeneity as a hallmark of tumour evolution and progression in hepatocellular carcinoma
Phuong H. D. Nguyen, Siming Ma, Cheryl Zi Jin Phua, Neslihan Arife Kaya, Hannah Lai, Chun Jye Lim, Jia Qi Lim, Martin Wasser, Liyun Lai, Wai Leong Tam, Tony Kiat Hon Lim, Wei Wan, Tracy Jiezhen Loh, Wei Qiang Leow, Yin Huei Pang, Chung Yip Chan, Ser Yee Lee, Peng Chung Cheow, Han Chong Toh, Florent Ginhoux, Shridhar Ganpathi Iyer, Alfred Wei Chieh Kow, Yock Young Dan, Alexander Chung, Glen K. Bonney, Brian K. P. Goh, Salvatore Albani, Pierce K. H. Chow, Weiwei Zhai, Valerie Chew
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.