PD-1 expression in hepatocellular carcinoma predicts liver-directed therapy response and bridge-to-transplant survival

Background: Hepatocellular carcinoma (HCC) patients undergo liver-directed therapy (LDT) to control tumor burden while awaiting liver transplantation with response impacting waitlist survival. In this study, we investigate the link between absolute lymphocyte count (ALC) and PD-1 expression with response to LDT and bridge-to-transplant survival.

Methods: Treatment-naïve HCC patients (n = 86) undergoing LDT were enrolled at a single center from August 2016-March 2020. Response to LDT was determined using mRECIST. Blood samples were collected on the day of LDT and at follow-up. Cells were analyzed for phenotype by flow cytometry. Outcomes were liver transplantation or tumor progression.

Results: Incomplete response to initial LDT was associated with tumor progression precluding liver transplantation (OR: 7.6, 1.7 - 33.3, P < 0.001). Univariate analysis of baseline T cell phenotypes revealed ALC (OR: 0.44, 0.24-0.85, P = 0.009) as well as intermediate expression of PD-1 on CD4 (OR: 3.3, 1.03-10.3, P = 0.034) and CD8 T cells (OR: 3.0, 0.99-8.8 P = 0.043) associated with incomplete response to LDT. Elevations in PD-1 expression were associated with increased risk of bridge-to-transplant tumor progression (HR: 3.2, 1.2-9.4). In patients successfully bridged to liver transplantation, pre-treatment peripheral PD-1 profile was associated with advanced tumor staging (P < 0.005) with 2/4 of patients with elevations in PD-1 having T3-T4 TNM staging compared to 0 with low PD-1 expression.

Conclusion: Low lymphocyte count or elevated expression of the PD-1 checkpoint inhibitor is associated with incomplete response to LDT and increased risk of bridge-to-transplant tumor progression. Patients with impaired T cell homeostasis may benefit from PD-1 immunotherapy to improve response to LDT and improve bridge-to-transplant outcomes.