High serum soluble CD155 level predicts poor prognosis and correlates with an immunosuppressive tumor microenvironment in hepatocellular carcinoma

Abstract

Background: Hepatocellular carcinoma (HCC) is one of the most prevalent malignancies with poor prognosis. There is no research about the clinical significance of serum soluble CD155 (sCD155) level for HCC. We aim to explore the prognostic and diagnostic value of sCD155 in HCC patients undergoing curative resection.

Methods: Serum sCD155 level in HCC patients was determined by enzyme-linked immunosorbent assay. The prognostic significance of sCD155 was evaluated by Cox regression and Kaplan-Meier analyses. CD155 expression and biomarkers of immune cells in HCC tissues were detected by immunohistochemistry staining. The diagnostic significance of sCD155 was evaluated using receiver operating characteristic curve.

Results: Serum sCD155 level was significantly increased in HCC patients and predicted poor prognosis. The prognostic value of sCD155 remained in low recurrent risk subgroups of HCC. Serum sCD155 level was positively related to CD155 expression in HCC tissues. High serum sCD155 level was associated with decreased numbers of CD8⁺ T cells and CD56⁺ NK cells and increased number of CD163⁺ M2 macrophages. Serum sCD155 level had better performance in distinguishing HCC patients from healthy donors and patients with chronic liver conditions than α-fetoprotein. Among patients with α-fetoprotein ≤ 20 ng/ml, serum sCD155 level could differentiate HCC patients from non-HCC patients.

Conclusion: Serum sCD155 level represents a promising biomarker for diagnosis and prognosis of HCC. High serum sCD155 level may reflect an immunosuppressive tumor microenvironment in HCC.

Keywords: biomarker; diagnosis; hepatocellular carcinoma; immunosuppression; prognosis; soluble poliovirus receptor.

FIGURE 1

Serum sCD155 level is elevated and associated with advanced tumor stage in HCC. A, Serum sCD155 level in groups of HCC, CIS, CHB, HD, and ICC. B, Serum sCD155 level in patients with different CNLC stages. C, Percentages of sCD155^low or sCD155^high HCC patients in different CNLC stages. *p value < 0.05, **p value < 0.01, and ***p value < 0.001

FIGURE 2

Serum sCD155 level is prognostically significant. A‐C, Correlation between serum sCD155 level and clinical characteristics of HCC patients (n = 148). D, Serum sCD155 level in HCC patients with or without recurrence. E‐G, Kaplan–Meier analysis of TTR of HCC patients in entire HCC cohort, single tumor lesion subgroup and AFP ≤ 20 ng/ml subgroup according to serum sCD155 level. *p value < 0.05, **p value < 0.01, and ***p value < 0.001

FIGURE 3

Metanalysis plot of univariate and multivariate Cox proportional regression analysis of factors associated with recurrence. A, Univariate analysis. B, Multivariate analysis

FIGURE 4

High serum sCD155 level correlates with an immunosuppressive TME in HCC. A, CD155 expression in HCC tissues was detected by IHC staining. Scale bar: 20 μm. B, Correlation between CD155 expression in HCC tissues and serum sCD155 level in corresponding blood samples. C, Representative IHC staining images of CD8⁺, CD56⁺, FOXP3⁺, and CD163⁺ cells in HCC tissues. Scale bar: 20 μm. D, Numbers of CD8⁺, CD56⁺, FOXP3⁺ and CD163⁺ cells in HCC tissues of sCD155^high patients and sCD155^low patients, respectively. *p value < 0.05, **p value < 0.01, and ***p value < 0.001

FIGURE 5

The diagnostic value of serum sCD155 level in HCC. A, Correlation between serum sCD155 level and serum AFP level in HCC patients. B‐E, The diagnostic performance of sCD155 in distinguishing HCC patients from non‐HCC, HD, CHB, and CIS, respectively. F, Among patients with AFP ≤ 20 ng/ml, the diagnostic performance of sCD155 in distinguishing HCC patients from non‐HCC patients