951P - CA19-9-related macrophage polarization has prognostic value in patients with HCC after immune checkpoint inhibitor treatment

Background

The specific role of CA19-9 in the efficacy of immunotherapy for hepatocellular carcinoma (HCC) remains unclear. To investigate the effect of CA19-9 levels on patients with HCC undergoing anti-programmed death-1 (PD-1)/programmed cell death ligand 1 (PD-L1) treatment and explore the potential impact of CA19-9 on the tumor immune microenvironment.

Methods

This cohort study included 621 patients who received anti-PD-1/PD-L1 treatment in three centers. During immunotherapy, CA19-9 levels were measured and classified as either ≥35 U/mL (elevated) or <35 U/mL (normal) for clinical analysis. Data were analyzed from January 2017 to March 2023. Overall survival (OS) and progression-free survival (PFS) were evaluated using Kaplan–Meier estimates. This study also explored mechanisms underlying the effect of CA19-9 on HCC immunotherapy through bioinformatic analysis and in vivo experiments.

Results

Elevated CA19-9 levels (≥35 U/mL) were significantly associated with reduced PFS and OS. The 1-year and 2-year PFS rates were 53.3% and 29.1%, respectively, in the normal CA19-9 group and 16.9% and 11.3%, respectively, in the elevated CA19-9 group (p < 0.001). The 1-year and 2-year OS rates in the normal CA19-9 group were 90.5% and 75.5%, respectively, whereas those in the elevated CA19-9 group were 64.0% and 36.5%, respectively (p < 0.001). Multivariate analysis confirmed CA19-9 as an independent prognostic factor for both PFS and OS. In addition, we found macrophage infiltration to be positively correlated to the expression of FUT3, a key gene involved in CA19-9 synthesis. Furthermore, increased M2 macrophage levels and reduced M1 macrophage levels were noted in HCC samples with elevated CA19-9 levels. Further in vivo experiments indicated that blocking CA19-9 improved the efficacy of PD-1 treatment through the induction of M1-like polarization of macrophages.

Conclusions

Our findings demonstrate that the elevated CA19-9 levels in patients with HCC after immunotherapy are associated with dismal survival outcomes, highlighting the crucial role of CA19-9 in modulating the efficacy of immunotherapy, particularly through its effect on macrophage polarization.

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

M. Zhu.

Funding

Has not received any funding.

Disclosure

All authors have declared no conflicts of interest.