T cell exhaustion dynamics are linked to clinical outcomes in Hepatocellular Carcinoma

Question Hepatocellular Carcinoma (HCC) is a rising global health problem with limited treatment options and poor prognosis. Despite translation of immunotherapy into clinical parameters the immunobiology of hepatocellular carcinoma is poorly understood. Exhausted and liver-resident T cells have been identified in HCC patients but their role and clinical relevance remains unclear. We therefore aimed to assess the clinical impact of T cell exhaustion in HCC patients by using a system immune profiling approach based on newly developed transcriptomic and cytometric signatures.

Methods Comprehensive phenotypic and functional exhaustion profiling of the peripheral and intrahepatic immune compartment (tumor-surrounding and tumor microenvironment) was performed ex vivo on samples from 20 HCC patients using mass cytometry. Single-cell- and population based transcriptome profiles from published datasets of HCC resections were in silico assessed for signatures of T cell exhaustion and residency and their link to patient survival. Exhaustion and residency of exhausted T cells were further analyzed by immunohistochemistry and imaging mass cytometry.

Results High parametric phenotypic and functional analysis identified a significant enrichment of exhausted CD8+ T cells (TEX) in the tumor microenvironment. Interestingly, a subgroup of mainly PD-1 positive TEX showed a strong co-expression of CD103, a marker for tissue resident memory cells (TRM). Analysis of the relationship between TEX and TRM revealed a high enrichment of TEX at the expense of TRM linked to poorer patient survival. Of note these TEX showed a differential expression of multiple immune checkpoint targets in the tumor microenvironment. In line with a potential protective role of TRM, survival analysis indicated that a higher TRM fraction of TEX was positively associated with progression free survival. These findings were confirmed by in silico analysis of exhaustion and residency signatures in TCGA HCC samples.

Conclusion These data demonstrate the clinical relevance of an exhausted T cell response in HCC patients. The dynamics between exhausted and resident liver T cells have implications for immune-based diagnostics, rational patient selection and monitoring during HCC immunotherapies. Based on these findings we propose the displacement of TRM by TEX in HCC as a novel clinically relevant pathophysiological concept.

Publication History

Article published online:
04 January 2021