Intratumoral heterogeneity and clonal evolution in liver cancer

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, TCRseq 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 singlebiopsy 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.

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

“…It was previously described that distinct histological TME could impact on clinical outcome of HCC 10,11 , whereas multiomic analyses also described intensive ITH in TME of HCC 12 . Other recent studies using immunogenomics approach addressed how the immune landscape contributes to genomic ITH in ovarian cancer 13 and HCC 14 . Despite all that, the clinical impact and role of immune-ITH in tumour evolution remain unexplored.…”

Genetics of Hepatocellular Carcinoma: Approaches to Explore Molecular Diversity

“…( 45 ) Nevertheless, recent immunogenomic approaches on multiregional HCC samples have shown a close relationship between regional adaptive immune response and tumor heterogeneity. ( 48 )…”

Breakthrough concepts in immune-oncology: Cancer vaccines at the bedside

“…369 An extensive genomic characterization carried out in glioblastoma patients identified differences in mutations in responders versus non-responders to immune checkpoint inhibitors. 370 These tumor heterogeneity issues have been extensively discussed elsewhere [371][372][373][374][375][376][377][378][379] and highlighted in several recent research articles 366,[380][381][382][383] and are beyond the scope of this review. Unless carefully detected and characterized, these factors can have detrimental effects by misdirecting treatment decisions.…”