Bahrami Pegah, Al Zein Mohammad, Eid Ali H, Sahebkar Amirhossein
Applied Biomedical Research Center, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran.
Faculty of Medical Sciences, Lebanese University, Beirut, Lebanon.
J Clin Exp Hepatol. 2025 Sep-Oct;15(5):102558. doi: 10.1016/j.jceh.2025.102558. Epub 2025 Mar 27.
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 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.
结直肠癌（CRC）、胃肠胰神经内分泌肿瘤（GEP-NEN）和胆管癌（CCA）一旦转移至肝脏，其发病率和死亡率都很高。对于经过严格筛选的患者，肝移植（LT）是治疗这些癌症的一种可行方法；然而，这些癌症在晚期具有侵袭性，导致许多患者被排除在移植名单之外或需要进一步降期。免疫检查点调节剂免疫疗法彻底改变了癌症研究。免疫检查点抑制剂（ICI）利用慢性炎症状态以及恶性细胞和调节性T细胞对细胞毒性T淋巴细胞抗原4（CTLA-4）和程序性细胞死亡蛋白1（PD-1）/程序性细胞死亡配体1（PD-L1）的过度表达，来阻断免疫检查点并抵消肿瘤逃避免疫系统的能力。然而，在肝移植病例中，同种异体移植物PD-L1与浸润性T细胞上的PD-1之间的相互作用是移植物耐受的一种方式。因此，ICI的应用可能会阻断这种保护作用并诱导移植物排斥，这一现象在抑制PD-1/PD-L1的ICI中尤为明显。通过应用先进的生物标志物并明确某些突变来加强肝移植前ICI使用的患者选择标准，可以减轻肝移植后移植物排斥的风险。此外，确定肝移植前后ICI给药的最佳间隔时间、确定肝移植后发生的恶性肿瘤中ICI的适应症，以及研究早期排斥检测的生物标志物，为CRC、GEP-NEN或CCA患者获得更有前景的肝移植结果铺平了道路。因此，本综述旨在通过展示ICI疗法在肝移植前后状态下的应用潜力以及减少或及时检测ICI相关移植物排斥的途径，全面概述ICI疗法在非肝细胞癌移植肿瘤学癌症管理中的作用。
