Liver Transplantation for Hepatocellular Carcinoma in the Era of Immune Checkpoint Inhibitors

Abstract

Hepatocellular carcinoma (HCC) remains the leading oncological indication for liver transplantation (LT), with evolving and broadened inclusion criteria. Immune checkpoint inhibitors (ICIs) gained a central role in systemic HCC treatment and showed potential in the peri-transplant setting as downstaging/bridging therapy before LT or as a treatment for HCC recurrence following LT. However, the antagonistic mechanisms of action between ICIs and immunosuppressive drugs pose significant challenges, particularly regarding the risk of acute rejection (AR). This review analyzes the main signaling pathways targeted by ICI therapies and summarizes current studies on ICI therapy before and after LT. The literature on this topic is limited and highly heterogeneous, precluding definitive evidence-based conclusions. The use of ICIs before LT appears promising, provided that a sufficient wash-out period is implemented. In contrast, the results of post-LT ICI therapy do not support its wide clinical application due to high AR rates and overall poor response to treatment. In the future, modern graft preservation techniques might support the selection of good ICI responders, but data from high-level studies are urgently needed.

Keywords: acute rejection; hepatocellular carcinoma; immune checkpoint inhibitors; immunotherapy; liver transplantation.

Figure 1

Overlapping pathways between ICIs and immunosuppressive drugs on T-cell activation. Both PD-1/PD-L1 and CTLA-4 blockades by ICIs result in activation of TCR and mTOR signaling, eventually upregulating NFAT, NF-kB, and AP-1 genes to further promote T-cell proliferation and cytokine expression. In contrast, immunosuppressive drugs, either targeting mTOR or directly interfering with the expression of the aforementioned genes, result in suppression of T-cell activation.

Figure 2

Computed tomography arterial (A) and portal (B) phase of a case of successful downstaging by a combination of loco-regional therapies and immunotherapy. After a microwave ablation of a Sg8 HCC, the patient developed a neoplastic thrombosis of Sg8 Glissonean pedicle. He was treated with trans-arterial radio-embolization followed by 20 cycles of Atezolizumab–Bevacizumab. After disappearance of contrast-enhancing tissue at the Sg8 pedicle and normalization of alpha-fetoprotein (from 42.9 to 8.1 ng/mL), the patient was waitlisted for liver transplantation 1 month after the last administration of immunotherapy. He was transplanted 10 days after and had an uneventful postoperative course, with no sign of acute rejection. At 5-month follow-up, he had normal liver function and no evidence of recurrence.