Abstract
Background & aimsInflammation 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.MethodsImmunohistochemistry 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.ResultsIn 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.ConclusionsOur 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.Electronic supplementary materialThe online version of this article (doi:10.1186/s13046-015-0247-1) contains supplementary material, which is available to authorized users.
Highlights
Background & aimsInflammation is a hallmark of cancer, yet the mechanisms that regulate immune cell infiltration into tumors remain poorly characterized
Our findings show that the CXC receptor 2 (CXCR2)–CXC ligand 1 (CXCL1) axis is correlated with CD15+ neutrophil infiltration into both intra- and peri-tumoral regions, and represents an independent prognostic factor in hepatocellular carcinoma (HCC)
Equal concentrations of total RNA were used in reverse transcription reactions to generate cDNA using a miScript Reverse Transcription Kit (Qiagen, Hilden, Gemany), each cDNA was used in SYBR Green real-time quantitative PCR according to standard protocols; primer sequences are listed in Additional file 1: Table S1
Summary
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. We found that neutrophils accumulated in the peri-tumoral regions of HCC where they promoted angiogenesis by releasing MMP9 [13]. The density of macrophages and neutrophils were both correlated with patient prognoses in HCC. It remains unclear how these diverse types of immune cells can be selectivity recruited to different tumor sites
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