BackgroundTransarterial chemoembolization (TACE) stands for the most commonly utilized therapy for hepatocellular carcinoma (HCC) worldwide. This study was to explore the potential predictive and prognostic roles of LAG-3 and PD-L1 as serum biomarkers in HCC patients underwent TACE treatment.MethodsA total of 100 HCC patients receiving TACE as well as 30 healthy controls were enrolled in the study. Serum LAG-3 and PD-L1 levels were determined at baseline and 3 day after TACE using enzyme-linked immunosorbent assay (ELISA).ResultsWe found serum levels of LAG-3 and PD-L1 were significantly elevated in HCC patients compared with healthy controls. Interestingly, patients with low pre-TACE and post-TACE levels of LAG-3 but not PD-L1 had a high probability of achieving an objective response (OR) after TACE treatment. Additionally, high pre-TACE LAG-3 level was correlated with poor disease outcome, and the patients with both high serum LAG-3 and PD-L1 level had the shorter overall survival (OS) than patients who are either PD-L1 or LAG-3 high or both PD-L1 and LAG-3 low. High pre-TACE serum LAG-3 level was positively associated with more cirrhosis pattern, advanced BCLC stage, pre-TACE alanine aminotransferase (ALT) level, and pre-TACE aspartate aminotransferase (AST) level. Furthermore, in 50 patients who underwent TACE, the serum LAG-3 level was significantly decreased at 3 day after TACE.ConclusionBoth pre-TACE and post-TACE serum LAG-3 levels could serve as powerful predictors for tumor response of TACE, and high pre-TACE serum LAG-3 level was an indicator for poor prognosis in HCC.
Understanding the details of metabolic reprogramming in hepatocellular carcinoma (HCC) is critical to improve stratification for therapy. Both multiomics analysis and cross-cohort validation were performed to investigate the metabolic dysregulation of 562 HCC patients from 4 cohorts. On the basis of the identified dynamic network biomarkers, 227 substantial metabolic genes were identified and a total of 343 HCC patients were classified into 4 heterogeneous metabolic clusters with distinct metabolic characteristics: cluster 1, the pyruvate subtype, associated with upregulated pyruvate metabolism; cluster 2, the amino acid subtype, with dysregulated amino acid metabolism as the reference; cluster 3, the mixed subtype, in which lipid metabolism, amino acid metabolism, and glycan metabolism are dysregulated; and cluster 4, the glycolytic subtype, associated with the dysregulated carbohydrate metabolism. These 4 clusters showed distinct prognoses, clinical characteristics and immune cell infiltrations, which was further validated by genomic alterations, transcriptomics, metabolomics, and immune cell profiles in the other 3 independent cohorts. Besides, the sensitivity of different clusters to metabolic inhibitors varied depending on their metabolic features. Importantly, cluster 2 is rich in immune cells in tumor tissues, especially programmed cell death protein 1 (PD-1)-expressing cells, which may be due to the tryptophan metabolism disorders, and potentially benefiting more from PD-1 treatment. In conclusion, our results suggest the metabolic heterogeneity of HCC and make it possible to treat HCC patients precisely and effectively on specific metabolic characteristics.
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