Immunotherapy in liver transplantation for hepatocellular carcinoma: Pros and cons

Abstract

Liver transplantation (LT) has emerged as a curative strategy for hepatocellular carcinoma (HCC), but contributes to a higher predisposition to HCC recurrence in the immunosuppression context, especially for tumors beyond the Milan criteria. Although immunotherapy has dramatically improved survival for immunocompetent patients and has become the standard of care for a variety of tumors, including HCC, it is mainly used outside the scope of organ transplantation owing to potentially fatal allograft rejection. Nevertheless, accumulative evidence has expanded the therapeutic paradigms of immunotherapy for HCC, from downstaging or bridging management in the pretransplant setting to the salvage or adjuvant strategy in the posttransplant setting. Generally, immunotherapy mainly includes immune checkpoint inhibitors (ICIs), adoptive cell transfer (ACT) and vaccine therapy. ICIs, followed by ACT, have been most investigated in LT, with some promising results. Because of the complex tumor microenvironment and immunoreactivity when immunosuppressants are combined with immunotherapy, it is difficult to reach formulations for immunosuppressant adjustment and the optimal selection of immunotherapy as well as patients. In addition, the absence of effective biomarkers for identifying rejection and tumor response is still an unresolved barrier to successful clinical immunotherapy applications for LT. In this review, we comprehensively summarize the available evidence of immunotherapy used in LT that is specific to HCC. Moreover, we discuss clinically concerning issues regarding the concurrent goals of graft protection and antitumor response.

Keywords: Hepatocellular carcinoma, Liver transplantation, Immunotherapy, Immune checkpoint inhibitors, Adoptive cell transfer, Immunosuppressant

Core Tip: This review addresses revolutionized immunotherapy for hepatocellular carcinoma (HCC) in liver transplantation (LT), from downstaging or bridging management in the pretransplant setting to adjuvant or salvage strategy in the posttransplant setting. Considering that the benefit of the antitumor response outweighs the incremental risk of rejection, it is worthwhile to take immunotherapy into account as the salvage option when HCC recurs after LT. More prospective studies are required to provide direct evidence regarding immunosuppressant adjustment, biomarkers for response and the optimal selection of immunotherapy as well as patients.