Hepatocellular carcinoma (HCC) is a leading cause of cancer-related deaths worldwide with no curative options for advanced stage. T cell-based immunotherapies have significantly improved overall survival rates, however response rates still remain low. Our aim is to identify novel antigenic targets and immune-signatures that can facilitate the identification and isolation of neoantigen reactive-T cell receptors (TCR) as potential immunotherapy for HCC. Clinical samples including primary liver tumors, liver flush, draining lymph nodes and peripheral blood lymphocytes (PBL) were collected from 16 HCC patients undergoing liver transplantation at Karolinska University hospital. Autologous T cells and antigen-presenting cells were isolated for in vitro functional assays. Samples from matched tumor and peripheral blood underwent whole exome and RNA sequencing to identify tumor-specific somatic mutations. A personalized immuno-oncology ranking analysis tool was employed to select promising neoantigen candidates for in vitro immunogenicity assessment. Neoantigen-reactive T cells expressing CD137 were isolated through FACS sorting and subjected to TCR sequencing. Single-cell RNA sequencing using 10X Genomics was performed to profile antigen-experienced T cells isolated from the patients tumors, liver flush, and lymph nodes.