Prolonged Survival of Human Hepatocarcinoma Cells in the Liver of Newborn C57BL/6 Mice and Resulting Cellular Xenorejection, Especially the Activation of Hepatic Natural Killer T Cells

• Published in: Pathobiology (Basel) Vol. 77; no. 3; pp. 115 - 128
• Main Authors: Du, Xiumin, Bai, Zengliang, Zhang, Jingping, Liu, Lanlan, Han, Ying, Wang, Ze, Huan, Tianxiao, Wu, Baojun
• Format: Journal Article
• Language: English
• Published: Basel, Switzerland S. Karger AG 01.01.2010
• Subjects: Age Factors; Animals; Animals, Newborn; Antigens, CD1d - immunology; Apoptosis; Cancer; Carcinoma, Hepatocellular - immunology; Carcinoma, Hepatocellular - pathology; CD3 Complex - immunology; Cell Survival; Cells; Cyclosporine - pharmacology; Cytotoxicity; Graft Survival - drug effects; Hep G2 Cells; Humans; Immunity, Cellular; Immunosuppressive Agents - pharmacology; Interferon-gamma - blood; Interleukin-4 - blood; Liver - drug effects; Liver - immunology; Liver - pathology; Liver Neoplasms - immunology; Liver Neoplasms - pathology; Lymphocyte Activation - drug effects; Lymphocytes; Lymphocytes, Tumor-Infiltrating - drug effects; Lymphocytes, Tumor-Infiltrating - immunology; Mice; Mice, Inbred C57BL; Natural Killer T-Cells - drug effects; Natural Killer T-Cells - immunology; Neoplasm Transplantation; Original Paper; Rodents; Spleen - immunology; Time Factors; Transplantation, Heterologous; Tumor Escape - drug effects; Tumors; Tumor xenografts; Hepatocellular carcinoma; Natural killer T cell; CD1d; Cyclosporin A; Cellular rejection
• ISSN: 1015-2008; 1423-0291
• DOI: 10.1159/000292645

Objective: To investigate the fate of human hepatocellular carcinoma (HCC) in the livers of newborn mice and the resulting cellular rejection.Methods: Two HCC cell lines (HepG2 and HCCLM3) labeled with DMAHAS were orthotopically transplanted to newborn and adult mice with or without low-dose cyclosporin A (CsA) treatment (10 mg/kg). The fate of tumor xenografts was examined and the resulting cellular response was investigated. Results: Tumor xenografts survived in newborn mice for >4 weeks, with a delayed lymphocyte infiltration mediated by CD4+ T, CD8+ T and NK1.1+ cells. In contrast, the xenografts survived in adults <8–10 days with an acute cellular rejection by CD8+T cells, NK1.1+ cells, macrophages or neutrophils. Orthotopic transplantation of human HCC xenografts elicited a strong cytotoxic response in newborn mice (p < 0.05), and selective T/NK1.1+ cell deletion in vitro suggested that such effector cells were mainly CD8+ T cells. Moreover, tumor xenografts induced a rapid activation of hepatic natural killer T (NKT) cells in both newborn and adult mice with enhanced secretion of IL-4 and IFN-γ in serum and subsequent NKT-like cytotoxicity. The rapid activation of NKT cells could be efficiently suppressed by low-dose CsA treatment, possibly in a CD1d-independent manner. Conclusion:Our data suggest that the livers of newborn mice were more suitable for the survival of xenografts than those of adult mice. Cell-mediated tumor xenorejection in newborn mice was different from that in adults, and hepatic NKT cells may play an important role in early tumor xenorejection.