Extracellular NAD+ levels are associated with CD203a expression on Th17 cells and predict long-term recurrence-free survival in hepatocellular carcinoma

J Cancer Res Clin Oncol. 2025 Mar 19;151(3):115. doi: 10.1007/s00432-025-06155-4.

Abstract

Background and aims: Mortality rates for hepatocellular carcinoma (HCC) remain high, while multimodal treatment approaches offer new perspectives. Here, we investigated the association of extracellular nicotinamide adenine dinucleotide (eNAD+) on ecto-nucleotide pyrophosphatase/phosphodiesterase 1 (CD203a, ENPP1 or PC-1) on Th17 cells in relation to the likelihood of HCC recurrence following liver resection.

Method: The study compared heparinized blood plasma samples from 95 patients who underwent liver resection, including 25 patients with HCC and 24 control patients without liver disease. Plasma eNAD+ concentrations were determined using a heat-based dichotomous pH extraction method, followed by enzymatic cycling and a colorimetric assay for quantification. Fibrosis was graded histologically using the Desmet score (F0-F4). Surface expression analysis was performed using flow cytometry.

Results: With increasing grades of liver fibrosis predominant in HCC patients, a significant reduction in plasma eNAD+ concentrations was measured (p < 0.05). Further, a significant correlation was found between HCC patients and CD203a expression on CD4+, CCR4+ as well as CCR6+ T cells (p < 0.05). Patients who exhibited high proportions of CD203a expressing Th17 cells (CD4+, CCR6+ CCR4+) post surgery were found to be at a sixfold increased risk (HR 6.38, 95% Cl 1.51-27.00) of HCC recurrence and had a median recurrence-free survival of 233 days (p < 0.05), compared to patients with low CD203a expressing Th17 cells (CD4+ CCR6+ CCR4+). Similarly, patients who had a high proportion of CD203a expressing Th17 cells (CD4+ CCR6+) following surgery had a fivefold increased risk (HR 5.56, 95% Cl 1.58-19.59) of HCC recurrence and a median recurrence-free survival of 334 days (p < 0.05) compared to those with low CD203a expressing Th17 cells (CCR6+).

Conclusion: The data indicates that eNAD+ levels are decreased in patients with liver fibrosis or cirrhosis. Strikingly, patients with high CD203a expression on Th17 cells had a significantly increased likelihood of recurrence, highlighting its potential as a valuable prognostic marker and a possible therapeutic target.

Keywords: CD203a; Hepatocellular cancer; Liver fibrosis; NAD+; Th17 cells.

MeSH terms

  • Adult
  • Aged
  • Apyrase
  • Biomarkers, Tumor
  • Carcinoma, Hepatocellular* / blood
  • Carcinoma, Hepatocellular* / immunology
  • Carcinoma, Hepatocellular* / metabolism
  • Carcinoma, Hepatocellular* / mortality
  • Carcinoma, Hepatocellular* / pathology
  • Carcinoma, Hepatocellular* / surgery
  • Disease-Free Survival
  • Female
  • Humans
  • Liver Cirrhosis / pathology
  • Liver Neoplasms* / blood
  • Liver Neoplasms* / immunology
  • Liver Neoplasms* / metabolism
  • Liver Neoplasms* / mortality
  • Liver Neoplasms* / pathology
  • Liver Neoplasms* / surgery
  • Male
  • Middle Aged
  • Neoplasm Recurrence, Local* / metabolism
  • Neoplasm Recurrence, Local* / pathology
  • Phosphoric Diester Hydrolases* / metabolism
  • Prognosis
  • Pyrophosphatases* / metabolism
  • Th17 Cells* / immunology
  • Th17 Cells* / metabolism

Substances

  • Pyrophosphatases
  • Phosphoric Diester Hydrolases
  • Biomarkers, Tumor
  • ENTPD1 protein, human
  • Apyrase