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. 2015 Oct 26:34:129.
doi: 10.1186/s13046-015-0247-1.

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

Li Li  1   2 , Li Xu  1 , Jing Yan  1   3 , Zuo-Jun Zhen  2 , Yong Ji  2 , Chao-Qun Liu  1 , Wan Yee Lau  2   4 , Limin Zheng  5 , Jing Xu  6
Affiliations

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

Li Li et al. J Exp Clin Cancer Res. .

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.

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Figures

Fig. 1
Fig. 1
In situ CXCR2 expression in HCC tumors. a Representative images show CXCR2+ cells stained brown in non-tumor (NT), peri-tumoral stroma (PS), and intra-tumor (IT) regions in HCC tissues. Black arrows indicate CXCR2+ cells. b The densities of CXCR2+ cells in the NT, PS, and IT regions of HCC tissues were calculated (n = 259). Results are expressed as means ± SEM (bars) of each group. c Multiple stains for CD15, CD68, CD3, or S100 (red), CXCR2 (green), and DAPI (blue) in paraffin-embedded sections were developed using a TSA system. White arrows indicate representative cells that express CXCR2. d Vectra-Inform image analysis of the proportion of CXCR2+ cells among CD15+, CD68+, CD3+, or S100+ cells in HCC tissues (n = 30). Results are expressed as means ± SEM (bars). e Proportions of CD15+, CD68+, CD3+, or S100+ cells among CXCR2+ cells in HCC tissues (n = 30). Results are expressed as means ± SEM (bars); *, P <0.05; **, P <0.01; ***, P <0.001
Fig. 2
Fig. 2
Accumulation of CXCR2+ cells predicts poor survival in HCC. OS (top) and RFS (bottom) were estimated using the Kaplan–Meier method and compared using the log-rank test (n = 259)
Fig. 3
Fig. 3
Correlations between CXCL-1, −2, −5, and −8 expression and CD3+, CD15+, and CD68+ cell densities in HCC tissues. Correlation coefficients between CXCL-1, −2, −5, and −8 expression and densities of each immune cell subset are shown; *, P <0.05; **, P <0.01
Fig. 4
Fig. 4
Prognostic significance of the combined actions of CXCR2 and CXCL1 expression in association with RFS and OS. Kaplan–Meier curves illustrate the duration of RFS and OS according to the combination of CXCR2 and CXCL1 expression in non-tumoral (a), peri-tumoral stroma (b) and intra-tumoral (c) regions; *, P <0.05; **, P <0.01; ***, P <0.001
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