Liver Cancer
Copyright ©2005 Baishideng Publishing Group Co., Limited. All rights reserved.
World J Gastroenterol. Jan 14, 2005; 11(2): 164-170
Published online Jan 14, 2005. doi: 10.3748/wjg.v11.i2.164
Desensitization of T lymphocyte function by CXCR3 ligands in human hepatocellular carcinoma
Yu-Qing Liu, Ronnie T. Poon, Jeremy Hughes, Qin-Yu Li, Wan-Ching Yu, Sheung-Tat Fan
Yu-Qing Liu, Ronnie T. Poon, Qin-Yu Li, Wan-Ching Yu, Sheung-Tat Fan, Centre for the Study of Liver Disease and Department of Surgery, The University of Hong Kong, Pokfulam, Hong Kong, China
Jeremy Hughes, Phagocyte Laboratory, MRC Centre for Inflammation Research, University of Edinburgh, Edinburgh, United Kingdom
Author contributions: All authors contributed equally to the work.
Supported by the Sun C. Y. Research Foundation for Hepatobiliary and Pancreatic Surgery of the University of Hong Kong
Correspondence to: Dr. Ronnie T. Poon, Department of Surgery, University of Hong Kong, Queen Mary Hospital, 102 Pokfulam Road, Hong Kong, China. poontp@hkucc.hku.hk
Telephone: +86-852-28553641 Fax: +86-852-28175475
Received: April 4, 2004
Revised: April 8, 2004
Accepted: June 17, 2004
Published online: January 14, 2005
Abstract

AIM: Despite the presence of lymphocyte infiltration, human hepatocellular carcinoma (HCC) is typically a rapidly progressive disease. The mechanism of regulation of lymphocyte migration is poorly understood. In this study, we investigated various factors regulating T cell migration in HCC patients. We examined serum CXC chemokine levels in HCC patients and demonstrated the production of CXC chemokines by HCC cell lines. We determined the effect of both HCC patient serum and tumor cell conditioned supernatant upon lymphocyte expression of chemokine receptor CXCR3 as well as lymphocyte migration. Lastly, we examined the chemotactic responses of lymphocytes derived from HCC patients.

METHODS: The serum chemokines IP-10 (CXCL10) and Mig (CXCL9) levels were measured by cytometric bead array (CBA) and the tumor tissue IP-10 concentration was measured by ELISA. The surface expression of CXCR3 on lymphocytes was determined by flow cytometry. The migratory function of lymphocytes to the corresponding chemokines was assessed using an in vitro chemotactic assay. Phosphorylation of extracellular signal-regulated kinase (ERK) was determined by Western blot analysis.

RESULTS: Increased levels of IP-10 and Mig were detected in HCC patient serum and culture supernatants of HCC cell lines. The IP-10 concentration in the tumor was significantly higher than that in the non-involved adjacent liver tissues. HCC cell lines secreted functional chemokines that induced a CXCR3-specific chemotactic response of lymphocytes. Furthermore, tumor-cell-derived chemokines induced initial rapid phosphorylation of lymphocyte ERK followed by later inhibition of ERK phosphorylation. The culture of normal lymphocytes with HCC cell line supernatants or medium containing serum from HCC patients resulted in a significant reduction in the proportion of lymphocytes exhibiting surface expression of CXCR3. The reduction in T cell expression of CXCR3 resulted in reduced migration toward the ligand IP-10, and both CD4+ and CD8+ T cells from HCC patients exhibited diminished chemotactic responses to IP-10 in vitro compared to T cells from healthy control subjects.

CONCLUSION: This study demonstrates functional desensitization of the chemokine receptor CXCR3 in lymphocytes from HCC patients by CXCR3 ligands secreted by tumor cells. This may cause lymphocyte dysfunction and subsequently impaired immune defense against the tumor.

Keywords: Hepatocellular carcinoma; CXCR3 ligands