Abstract
BACKGROUND: Mass-forming (MF) type is the most common, accounting for 57.1-83.6% of intrahepatic cholangiocarcinoma (ICC), with a poor prognosis. Transarterial chemoembolization (TACE) can induce necrosis of tumor cells, induce the release of tumor antigens, enhance the immune response of tumor-specific CD8(+) T cells, and regulate the proliferation of Treg cells. However, real-world data directly comparing TACE combined with programmed cell death protein-1 (PD-1) versus programmed death ligand-1 (PD-L1) inhibitors in MF-ICC are lacking. Therefore, we aimed to evaluate the efficacy and safety between the different immune checkpoint inhibitors (ICIs) (PD-1/PD-L1 inhibitors) in MF-ICC, and to explore prognosis-related clinical factors and preliminary immune mechanisms underlying this combined therapy. METHODS: A total of 50 patients with MF-ICC who underwent TACE combined with ICIs at Beijing Friendship Hospital and Beijing Ditan Hospital from May 2020 to December 2024 were retrospectively enrolled. Least absolute shrinkage and selection operator (LASSO) regression was used to screen the risk factors of overall survival (OS). Survival was estimated using the Kaplan-Meier method and compared by the log-rank test. Univariable Cox proportional hazards models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for the association between treatment regimen and survival. In parallel, we analyzed dynamic changes in immune cells before and after ICI treatment using the single-cell RNA sequencing dataset GSE208205 and further validated these findings by flow cytometry. RESULTS: The median overall survival (mOS) and median progression-free survival (mPFS) for TACE-PD-L1 followed by therapy were 18 and 13 months, which were significantly longer than those with TACE-PD-1 sequential therapy (mOS: 12 months, HR: 0.42, 95% CI: 0.17-1.03, P=0.047; mPFS: 8 months, HR: 0.29, 95% CI: 0.12-0.73, P=0.006). In exploratory multivariable analysis, pre-treatment monocyte-to-lymphocyte ratio (MLR), Child-Pugh classification, total bilirubin (TBIL), and alanine aminotransferase (ALT) emerged as potential prognosis-related factors for OS. Single-cell analysis showed that CD4(+) T and CD8(+) T cells were markedly increased after treatment, while circulating tumor cells and vascular endothelial cells were decreased. This was further validated by the flow cytometry. Moreover, regardless of treatment status, ICC patients in the PD-L1 groups exhibited higher levels of CD4(+) and CD8(+) T cells compared to the PD-1 group, whereas B cells were lower in the PD-L1 group than in the PD-1 group. CONCLUSIONS: TACE combined with PD-L1 inhibitors was associated with longer survival than TACE combined with PD-1 inhibitors in patients with mass-forming ICC. The immune system, particularly lymphocytes, plays a critical role in the efficacy of combination therapy. In addition, several baseline inflammation- and liver function-related factors (MLR, Child-Pugh class, TBIL, ALT) were associated with OS in exploratory analyses.