CXCR2–CXCL1 axis is correlated with neutrophil infiltration and predicts a poor prognosis in hepatocellular carcinoma

Abstract

BACKGROUND & AIMS: Inflammation is a hallmark of cancer, yet the mechanisms that regulate immune cell infiltration into tumors remain poorly characterized. This study attempted to characterize the composition, distribution, and prognostic value of CXCR2(+) cells in hepatocellular carcinoma (HCC) and to examine the CXCR2 ligands that are responsible for local immune infiltration in different areas of HCC tumors. METHODS: Immunohistochemistry and immunofluorescene were used to identify CXCR2(+) cells in HCC tissues. Kaplan-Meier analysis and Cox regression models were applied to estimate recurrence-free survival (RFS) and overall survival (OS) for 259 HCC patients. The expression levels of CXCR2 ligands (CXCL-1, -2, -5, and -8) were measured by real-time PCR and compared with local immune cell density. The combined prognostic value of the CXCR2-CXCL1 axis was further evaluated. RESULTS: In HCC tissues, CXCR2(+) cells were mainly neutrophils that were enriched in the peri-tumoral stroma (PS) region. Kaplan-Meier survival analysis showed that increased CXCR2(+) PS cells were associated with reduced RFS and OS (P = 0.015 for RFS; P = 0.002 for OS). Multivariate Cox proportional hazards analysis identified CXCR2(+) PS cell density as an independent prognostic factor for OS (hazard ratio [HR] = 1.737, 95 % confidence interval [CI] = 1.167-2.585, P = 0.006). Furthermore, we detected a positive correlation between the density of CD15(+) neutrophils and CXCL1 levels in both the peri-tumoral stroma and intra-tumoral regions. The combination of CXCR2 and CXCL1 expression levels represented a powerful predictor of a poor prognosis for patients with HCC. CONCLUSIONS: Our data showed that the CXCR2(+) cell density was an independent prognostic factor for predicting OS for HCC patients. The CXCR2-CXCL1 axis can regulate neutrophil infiltration into HCC tumor tissues and might represent a useful target for anti-HCC therapies.