Weidi Wang, Tianyi Chen, Haoyu Wang, Jiayuan Zhao, Chen Yang, Yuxiao Wu, Yujia Kong, Dan Wang, Yuan Li, Junjun Yang, Yang Xiang
DIA-MS identified a resistance-associated plasma proteomic signature enriched in inflammatory and immunomodulatory mediators among patients with progressive disease. In the full-cohort ELISA assessment, elevated baseline plasma HLA-G and osteopontin (OPN) were associated with primary resistance. The exploratory two-marker model showed an apparent area under the receiver operating characteristic curve of 0.908. In the limited tissue subset, higher HLA-G expression tended to be associated with lower CD8-positive T-cell density, whereas higher OPN expression was associated with increased CD163-positive macrophage density. Public-dataset analyses provided supportive context for associations of HLA-G and SPP1 transcript expression with immune-related programs and unfavorable outcomes.
INTRODUCTION: Although programmed cell death protein 1 (PD-1) inhibitors combined with chemotherapy have improved outcomes in high-risk choriocarcinoma, primary resistance remains a clinically important challenge without reliable predictive biomarkers.
METHODS: We performed data-independent acquisition mass spectrometry (DIA-MS) on pretreatment plasma from a nested discovery subset of 30 patients, followed by enzyme-linked immunosorbent assay (ELISA) assessment of shortlisted candidates in the full cohort of 60 patients. An exploratory two-marker logistic model was developed and internally assessed in the same cohort. Exploratory tissue immunophenotyping and analyses of public tissue-transcriptomic and immunotherapy datasets were used to provide biological context.
RESULTS: DIA-MS identified a resistance-associated plasma proteomic signature enriched in inflammatory and immunomodulatory mediators among patients with progressive disease. In the full-cohort ELISA assessment, elevated baseline plasma HLA-G and osteopontin (OPN) were associated with primary resistance. The exploratory two-marker model showed an apparent area under the receiver operating characteristic curve of 0.908. In the limited tissue subset, higher HLA-G expression tended to be associated with lower CD8-positive T-cell density, whereas higher OPN expression was associated with increased CD163-positive macrophage density. Public-dataset analyses provided supportive context for associations of HLA-G and SPP1 transcript expression with immune-related programs and unfavorable outcomes.
DISCUSSION: Elevated circulating HLA-G and OPN are associated with resistance to PD-1 inhibitor plus chemotherapy in choriocarcinoma and may serve as candidate minimally invasive biomarkers for pretreatment risk stratification. Independent validation and functional investigation are required before clinical application.