Intratumoral heterogeneity and clonal evolution in liver cancer

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.