Liver Transplantation for Non-hepatocellular Carcinoma: The Role of Immune Checkpoint Inhibitors

Colorectal cancer (CRC), gastroenteropancreatic neuroendocrine neoplasm (GEP-NEN), and cholangiocarcinoma (CCA) exhibit high rates of morbidity and mortality once metastasized to the liver. Liver transplantation (LT) is a viable therapeutic approach for these cancers in highly selected patients; however, their invasive nature at late stages causes many patients to be delisted from transplantation or to require further downstaging. Immunotherapy with immune checkpoint modulators has revolutionized cancer research. Immune checkpoint inhibitors (ICI) leverage the chronic inflammatory state and the overexpression of cytotoxic T lymphocyte antigen 4 (CTLA-4) and programmed cell death protein 1 (PD-1)/programmed cell death-ligand 1 (PD-L1) by malignant cells and regulatory T cells, to block immune checkpoints and counteract tumor's ability to evade the immune system. However, the interaction between allograft PD-L1 and PD-1 on infiltrating T cells functions as a means of graft tolerance in cases of LT. Therefore, the application of ICIs might block this protective effect and induce graft rejection, a phenomenon particularly observed in PD-1/PD-L1 inhibiting ICIs. The risk of post-LT graft rejection can be mitigated by applying advanced biomarkers and specifying certain mutations that enhance patient selection criteria for pre-LT ICI use. Furthermore, the determination of optimal intervals of ICI administration pre- and post-LT, identification of ICI indications in de novo malignancies occurring after LT, and investigation of biomarkers for early rejection detection, pave the way for more promising LT outcomes in patients with CRC, GEP-NEN, or CCA. Therefore, this review aims to illustrate a comprehensive overview of the role of ICI therapy in the management of non-hepatocellular carcinoma transplant oncology cancers by demonstrating the potential for its application in both pre-and post-LT states, and pathways to reduce or timely detect ICI-associated graft rejection.