CXCR2-CXCL1 axis is correlated with neutrophil infiltration and predicts a poor prognosis in hepatocellular carcinoma.
OBJECTIVE
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.
Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, P. R. China.|Department of Hepatic & Pancreatic Surgery, The First People's Hospital of Foshan, Foshan, Guangdong, P. R. China.
Li
L
Li
Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, P. R. China.
Li
L
Xu
Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, P. R. China.|Department of Medicine, Division of Rheumatology, Immunology and Allergy, Brigham and Women's Hospital, One Jimmy Fund Way, Boston, MA, 02115, USA.
Jing
J
Yan
Department of Hepatic & Pancreatic Surgery, The First People's Hospital of Foshan, Foshan, Guangdong, P. R. China.
Zuo-Jun
ZJ
Zhen
Department of Hepatic & Pancreatic Surgery, The First People's Hospital of Foshan, Foshan, Guangdong, P. R. China.
Yong
Y
Ji
Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, P. R. China.
Chao-Qun
CQ
Liu
Department of Hepatic & Pancreatic Surgery, The First People's Hospital of Foshan, Foshan, Guangdong, P. R. China.|Faculty of Medicine, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong, SAR, P. R. China.
Wan Yee
WY
Lau
Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, P. R. China. zhenglm@mail.sysu.edu.cn.
Limin
L
Zheng
Department of Hepatic & Pancreatic Surgery, The First People's Hospital of Foshan, Foshan, Guangdong, P. R. China. xujing@sysucc.org.cn.
Jing
J
Xu
D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D006528:Carcinoma, Hepatocellular / Q000276:immunology* / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D045744:Cell Line, Tumor; D054360:Chemokine CXCL1 / Q000235:genetics / Q000378:metabolism*; D005260:Female; D015870:Gene Expression; D006801:Humans; D007150:Immunohistochemistry; D053208:Kaplan-Meier Estimate; D008111:Liver Function Tests; D008113:Liver Neoplasms / Q000276:immunology* / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D008297:Male; D008875:Middle Aged; D060787:Neoplasm Grading; D009364:Neoplasm Recurrence, Local; D009367:Neoplasm Staging; D020556:Neutrophil Infiltration / Q000276:immunology*; D011379:Prognosis; D023063:Receptors, Interleukin-8B / Q000235:genetics / Q000378:metabolism*; D047368:Tumor Burden; D055815:Young Adult
D054360:Chemokine CXCL1; D023063:Receptors, Interleukin-8B