Immune-Related Adverse Events Strongly Predict Post-Transplant Rejection After Pretransplant Immunotherapy in HCC : Gut | May 2026

Introduction

Hepatocellular Carcinoma management increasingly incorporates Immune Checkpoint Inhibitors for downstaging and bridging prior to Liver Transplantation. Although checkpoint inhibitors can successfully expand transplant eligibility and improve tumor control, they also create a major immunological dilemma because persistent immune activation may increase the risk of catastrophic post-transplant allograft rejection.

Problem Statement

Reliable predictors of post-transplant rejection after pretransplant immune checkpoint inhibitor exposure remain poorly defined, limiting safe patient selection and peri-transplant immunotherapy planning.

Summary

This national multicentre retrospective study evaluated predictors of allograft rejection in hepatocellular carcinoma patients receiving immune checkpoint inhibitors before liver transplantation, with particular emphasis on the role of immune-related adverse events (irAEs).

The study identified immune-related adverse events as the strongest independent predictor of post-transplant rejection. Patients experiencing irAEs during checkpoint inhibitor therapy had an approximately ninefold higher risk of subsequent allograft rejection after transplantation. This is a highly important and clinically actionable observation because irAEs may represent a real-time biomarker of sustained systemic immune activation.

Post-transplant rejection occurred in 17% of patients overall, typically developing early after transplantation, with a median onset of only 10 days. This rapid temporal pattern supports the concept that pre-existing activated immune pathways persist into the peri-transplant period despite surgical organ replacement and immunosuppression.

Additional independent risk factors included younger recipient age and shorter washout intervals below 30 days between checkpoint inhibitor exposure and transplantation. These findings align with previous concerns that insufficient immune de-escalation time before transplantation may leave residual T-cell activation capable of targeting the allograft.

Importantly, the study moved beyond clinical associations and explored mechanistic correlates through a prospective observational cohort. Patients developing irAEs demonstrated significantly increased circulating CD8+ T-cell populations and elevated inflammatory cytokines including IFN-α and TNF-α, suggesting a hyperactivated cytotoxic immune phenotype.

These data provide biologic plausibility for the observed clinical association between irAEs and rejection risk. Immune-related toxicities may not merely reflect isolated organ-specific inflammation but instead indicate a globally primed immune system capable of heightened alloimmune reactivity.

Clinically, the findings have major implications for transplant hepatology and multidisciplinary tumor boards. Occurrence of irAEs during checkpoint inhibitor therapy may need to be incorporated into transplant eligibility assessment, perioperative risk counseling and individualized immunosuppression planning.

The predictive model generated in the study achieved good discriminatory performance, suggesting that integrated risk stratification incorporating irAEs, recipient age and washout duration may help identify patients at particularly high rejection risk.

The study also contributes to the evolving discussion regarding optimal timing of transplantation after checkpoint inhibitor therapy. Although no universally accepted washout interval exists, these findings support caution with very short intervals, especially in patients who experienced clinically significant immune toxicities.

From an oncologic perspective, the work highlights the increasingly complex balance between maximizing antitumor immunity and preserving transplant tolerance. Checkpoint inhibitors may simultaneously improve tumor control while destabilizing alloimmune equilibrium.

The findings are especially relevant because checkpoint inhibitors are increasingly being used earlier in HCC treatment algorithms, including neoadjuvant and bridging settings. As immunotherapy exposure before transplantation becomes more common, reliable biomarkers for rejection prediction will become critically important.

The study further underscores the need for close collaboration between oncology, transplant hepatology and transplant immunology teams when managing these patients. Decisions regarding checkpoint inhibitor selection, duration, toxicity management and transplantation timing will likely require increasingly individualized approaches.

Overall, this multicentre study identifies immune-related adverse events as a powerful predictor of post-transplant rejection in HCC patients exposed to pretransplant checkpoint inhibitors. The findings suggest that irAEs may serve as clinically accessible markers of persistent immune activation and provide an important framework for risk stratification and peri-transplant immunotherapy management.