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 evolutio