Short- term prognosis of recipients with pretransplant exposure to immune checkpoint inhibitors after liver transplantation for hepatocellular carcinoma: A retrospective cohort study

Abstract

Background and aims: Despite growing evidence linking pretransplant exposure to immune checkpoint inhibitors (ICIs) to increased allograft rejection risk after livertransplantation (LT), a lack of comparative studies to definitively establish the correlation between ICI exposure and adverse short-term outcomes after LT exists. This study aimed to analyze the impact of preoperative ICI exposure on short-term post-LT prognosis and allograft rejection risk.

Methods: This retrospective cohort study included 121 recipients who underwent LT for hepatocellular carcinoma (HCC) between June 2019 and March 2023. The recipients were categorized into ICI (n = 35) and non-ICI (n = 86) exposure groups based on pretransplant ICI exposure. Demographics, clinical characteristics, and short-term outcomes were compared between the cohorts. Kaplan-Meier analysis evaluated the impact of ICI exposure on graft survival. Univariate and multivariate logistic regression models assessed the impact of patient characteristics on allograft rejection.

Results: Recipients with or without ICI exposure exhibited comparable demographic baseline characteristics. The incidences of early allograft dysfunction and biliary and vascular complications were similar between both groups. Post-transplant infection incidence was 37.1% and 20.9% in the ICI and non-ICI groups, respectively (P = 0.064). Allograft rejection rates were significantly higher in the ICI group than in the non-ICI group (22.9% vs. 5.8%, P = 0.015). The ICI group exhibited a higher 90-day post-transplant mortality rate than that of the non-ICI group (14.3% vs. 2.3%, P = 0.034). Logistic regression analyses demonstrated that allograft rejection independently correlated with 90-day post-transplant mortality, with ICI exposure being an independent risk factor for allograft rejection. In recipients with ICI exposure, a shorter interval between ICIs and LT (washout period) was significantly associated with a higher allograft rejection risk, with the optimal washout period identified as 21 days for predicting 90-day rejection-free survival (P = 0.0001). Moreover, in recipients with allograft rejection, the peripheral CD4⁺/CD8⁺ T cell ratio was much lower in the ICI group than in the non-ICI group.

Conclusions: Pretransplant ICI exposure was an independent risk factor for allograft rejection and was significantly associated with 90-day post-transplant mortality after LT for HCC. A ≤21-day washout period was significantly associated with allograft rejection. Future multicenter studies with larger cohorts and prospective designs are essential to validate these findings, confirm causality, and establish standardized clinical guidelines for ICI use before transplantation.

Keywords

Immune checkpoint inhibitors (ICIs) / Hepatocellular carcinoma (HCC) / Liver transplantation (LT) / Immunotherapy / Graft rejection / Post-transplant mortality / CD4-CD8 ratio

Data availability statement

All raw data generated in this study are available upon request from the corresponding authors. The study protocol, standard, operating procedure, and patient information are also available upon request.

Authors’ contributions

Li Pang and Leibo Xu contributed equally to this work and should be considered co-first authors. Li Pang: Writing e original draft, Resources, Methodology, Writing e review & editing, Conceptualization. Leibo Xu: Resources, Funding acquisition, Conceptualization. Zhijun Chen: Investigation, Methodology, Writing e review & editing. Yang Liu: Investigation, Methodology, Writing e review & editing. Tao Ding: Methodology, Writing e review & editing. Yanfang Ye: Methodology, Writing e review & editing. Xinjun Lu: Methodology, Resources. Guangxiang Gu: Methodology, Writing e review & editing. Haoming Lin: Methodology, Writing e review & editing, Resources. Wenrui Wu: Conceptualization, Writing e review & editing, Resources. Kwan Man: Conceptualization, Writing e review & editing. Chao Liu: Conceptualization, Funding acquisition, Resources.

Declaration of competing interest

The authors declare that there is no conflicts of interest.

Acknowledgements

This study was supported by the National Natural Science Foundation of China (No. 82472903, 82203747, 82173229, and 82173195); Guangzhou Key Laboratory of Precise Diagnosis and Treatment of Biliary Tract Cancer (No. 202201020375); China Postdoctoral Science Foundation (No. 2022TQ0388 and 2023M734036); Science and Technology Program of Guangzhou (No. 202102010326 and 2023A03J0700); Sun Yat-sen University Clinical Research 5010 Program (No. 2018008); Sun Yat-sen Me-morial Hospital Clinical Research 5010 Program (No. SYS-5010-202305); Sun Yat-sen Pilot Scientific Research Fund (SYSQH-II-2024-05).

Appendix A. Supplementary data

Supplementary data to this article can be found online at https://doi.org/10.1016/j.livres.2025.03.001.

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