Expression and function of CXC and CC chemokines in human malignant liver tumors: A role for human monokine induced by gamma-interferon in lymphocyterecruitment to hepatocellular carcinoma

Chemotactic cytokines (chemokines) play an important role in the recruitmen t of lymphocytes to tissue by regulating cellular adhesion and transendothe lial migration. This study examined the expression and function of CXC (hum an monokine induced by gamma-interferon [HuMig], interleukin-8 [IL-8], and interferon-inducible protein-10 [IP-10]) and CC (macrophage inflammatory pr otein-1 alpha [MIP-1 alpha], MIP-1 beta, regulated upon activation normal T lymphocyte expressed and secreted (RANTES), and macrophage chemoattractant protein-1 [MCP-1]) chemokines and their respective receptors on lymphocyte s infiltrating human liver tumors. Chemokine and chemokine receptor express ion was assessed by immunohistochemistry, flow cytometry, iii situ hybridiz ation and ribonuclease (RNAse) protection assays and function by in vitro c hemotaxis of tumor-derived lymphocytes to purified chemokines and to HepG2 tumor cell culture supernatants, Tumor-derived lymphocytes showed strong ch emotactic responses to both CC and CXC chemokines in vitro and expressed hi gh levels of CXCR3 (HuMig and IP-10 receptor) and CCR5 (RANTES, MIP-1 alpha , and MIP-1 beta receptor). Expansion of tumor-derived lymphocytes in recom binant IL-2 increased expression of CXCR3, The corresponding chemokines wer e detected on vascular endothelium (HuMig, IL-8, MIP-1 alpha, and MIP-1 bet a) and sinusoidal endothelium (HuMig, MIP-1 alpha, MIP-1 beta) in hepatocel lular carcinoma. In vitro, HepG2 cells secreted functional chemotactic fact ors for tumor-derived lymphocytes that could he inhibited using anti-CCR5 o r anti-CXCR3 monoclonal antibodies (MoAbs), Thus, lymphocytes infiltrating human liver tumors express receptors for and respond to both CXC and CC che mokines, The relevant chemokine ligands are expressed in hepatocellular car cinoma (HCC), particularly HuMig, which was strongly expressed by tumor end othelium, suggesting that they play a role in lymphocyte recruitment to the se tumors in vivo. The ability of HepG2 cells to secrete lymphocyte chemota ctic factors in vitro suggests that the tumor contributes to lymphocyte rec ruitment in vivo.