*Purpose: T cell receptor (TCR) sequencing in hepatocellular carcinoma (HCC) patients revealed a diverse TCR repertoire in hepatitis B-associated HCC-infiltrating T cells. In this study, we investigate changes in TCR diversity in both viremic and nonviremic hepatitis C-associated HCC (HCV-HCC) patients following liver-directed therapy (LDT) and links to bridge to transplant waitlist outcome.

*Methods: HCV-HCC patients receiving LDT as a bridge to liver transplantation were prospectively enrolled at a high-volume transplant center. Peripheral blood T cells were characterized by flow cytometry at baseline and treatment follow-up as well as longitudinally while on the waitlist. T cell DNA isolated at each time point was sequenced and analyzed using ImmunoSeq Analyzer (Adaptive Biotechnologies). Response to LDT was assessed by mRECIST.

*Results: The cohort (n=17) was stratified based on HCV status (viremic n=10 and nonviremic n=7). Only 3 TCR clonotypes were shared over the entire cohort. Viremic HCV was associated with a more diverse T cell repertoire prior to and following LDT (P=0.007 and P=0.032). LDT resulted in a treatment-dependent increase in TCR diversity (P=0.034) and unique TCR clonotypes at follow-up independent of response to LDT. TCR diversity was strongly correlated with T cell senescence (CD57) as well as the PD-1 checkpoint inhibitor pathway in both CD4 (P=0.009 and P=0.037) and CD8 T cells (P=0.016 and P=0.019), respectively. Low TCR diversity following LDT was also associated with waitlist tumor progression (P=0.015). In patients successfully bridged to liver transplantation, 2.3-10.4% of intratumoral T cell clonotypes found in explant tumors were also found in circulating T cells prior to LDT. The percentage of clonotype overlap between TILs and circulating T cells did not change following treatment.

*Conclusions: The TCR repertoire is diverse in HCV-HCC patients and shifted based on viremic HCV status and LDT. HCV-HCC patients with low TCR diversity following treatment are at greater risk of tumor progression which may be mediated by T cell senescence and checkpoint inhibitory pathways. Longitudinal TCR profiling may uncover unique HCC biology or treatment pathways linked to effective neoantigen responses and improved bridge to transplant outcomes.

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