Genomic and transcriptional Profiling of tumor infiltrated CD8+ T cells revealed functional heterogeneity of antitumor immunity in hepatocellular carcinoma

As key players in HCC antitumor response, the functions of tumor infiltrated CD8(+) T cells are significantly affected by surrounding microenvironment. A detailed profiling of their genomic and transcriptional changes could provide valuable insights for both future immunotherapy development and prognosis evaluation. We performed whole exome and transcriptome sequencing on tumor infiltrated CD8(+) T cells and CD8(+) T cells isolated from other tissue origins (peritumor tissues and corresponding PBMCs) in eight treatment-naive HCC patients. The results demonstrated that transcriptional changes, rather than genomic alterations were the main contributors to the functional alterations of CD8(+) T cells in the process of tumor progression. The origins of CD8(+) T cells defined their transcriptional landscape, while the tumor infiltrated CD8(+) T cells shared more similarity with peritumor-derived CD8(+) T cells compared with those CD8(+) T cells in blood. In addition, tumor infiltrated CD8(+) T cells also showed larger transcriptional heterogeneity among individuals, which was modulated by clinical features such as HBV levels, preoperative anti-viral treatment and the degree of T cell infiltration. We also identified multiple inter-connected pathways involved in the activation and exhaustion of tumor infiltrated CD8(+) T cells, among which IL-12 mediated pathway could dynamically reflect the functional status of CD8(+) TILs and activation of this pathway indicated a better prognosis. Our results presented an overview picture of CD8(+) TILs' genomic and transcriptional landscape and features, as well as how the functional status of CD8(+) TILs correlated with patients' clinical course.