Molecular regulation of NK cell cytotoxicity fir human hepatocellular carcinoma

• Project/Area Number: 18390216
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Gastroenterology
• Research Institution: Osaka University
• Principal Investigator: TAKEHARA Tetsuo Osaka University, Graduate School of Medicine, Associate Professor (70335355)
• Co-Investigator(Kenkyū-buntansha): HIRAMATSU Naoki Osaka University, Graduate School of Medicine, Assistant Professor (30362700) ; TATSUMI Tomohide Osaka University, Hospital, Assistant Professor (20397699)
• Project Period (FY): 2006 – 2007
• Project Status: Completed (Fiscal Year 2007)
• Budget Amount: ¥11,850,000 (Direct Cost: ¥10,500,000、Indirect Cost: ¥1,350,000); Fiscal Year 2007: ¥5,850,000 (Direct Cost: ¥4,500,000、Indirect Cost: ¥1,350,000); Fiscal Year 2006: ¥6,000,000 (Direct Cost: ¥6,000,000)
• Keywords: MICA / NKG2D / HCC / NK receptor / Liver / Tumor / Innate immunity / MICB / TAE / 自然免 / MICB / Soluble MICA / Soluble MICB

Research Abstract

Soluble forms of MHC class I-related chain A and B (MICA/B) increase in sera of patients with malignancy and impair the anti-tumor immune response by downregulating expression of their cognate immunoreceptor NKG2D. Recently, soluble MICA/B were reported to appear even in some premalignant diseases, raising the question about the impact of soluble MICA/B produced from tumors on the expression of NKG2D. The present study examined soluble MICA/B in chronic liver disease and hepatocellular carcinoma (HCC) and their involvement in the immune cell expression of NKG2D during transcatheter arterial embolization (TAE) for HCC. The levels of soluble MICA/B were significantly higher in chronic liver disease and HCC patients than in healthy volunteers. The progression of liver disease and that of the tumor were independent determinants for soluble MICA/B levels. Immunohistochemistry revealed that MICA/B was expressed not only in HCC tissue but also on hepatocytes in cirrhotic livers. The TAE therapy significantly decreased serum levels of soluble MICA, but not soluble MICB, and increased the NKG2D expression on NK cells and CD8-positive T cells; there was an inverse correlation between changes in soluble MICA levels and in NKG2D expression. In vitro experiments confirmed that MICA-containing sera clearly downregulated NKG2D expression and suppressed NKG2D-mediated effector cell function. In conclusion, although soluble MICA/B are produced from both HCC and premalignant cirrhotic livers, therapeutic intervention for HCC can reduce the levels of soluble MICA and thereby upregulate the expression of NKG2D. Cancer therapy may have a beneficial effect on the NKG2D-mediated anti-tumor immunity.

Research Products

• [Journal Article] Innate immunity in type C hepatitis. Hepatitis C virus disease (2008)
  • Author(s): Takehara, T., Hayashi, N
  • Pages: 1-15
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Natural killer cell and hepatic cell interaction via NKG2A leads to dendritic cell-mediated induction of CD4+ CD25+ T cells with PD-1-dependent regulatory activities. (2007)
  • Author(s): Jinushi M, Takehara T, et. al.
  • Journal Title: Immunology 120 Pages: 73-82
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] Intrahepatic delivery of α-galactosylceramide-pulsed dendritic cells suppresses liver tumor. (2007)
  • Author(s): Tatsumi T, Takehara T, et. al.
  • Journal Title: Hepatology 45 Pages: 22-30
  • NAID: 40015716465
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] Natural Killer cell-mediated ablation of metastatic liver tumors by hydrodynamic injection of IFNα gene to mice. (2007)
  • Author(s): Takehara T, Uemura A, et. al.
  • Journal Title: International Journal of Cancer 120 Pages: 1252-1260
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] Intrahepatic delivery of α-galactosylceramide-pulsed dendritic cells suppresses liver tumor (2007)
  • Author(s): Tatsumi, T., Takehara, T., Yamaguchi, S., Sasakawa, A., Sakamori, R., Ohkawa, K., Kohga, K., Uemura, A., Hayashi, N
  • Journal Title: Hepatology 45 Pages: 22-30
  • NAID: 40015716465
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Natural killer cell and hepatic cell interaction via NKG2A leads to dendritic cell-mediated induction of CD4+ CD25+ T cells with PD-1-dependent regulatory activities (2007)
  • Author(s): Jinushi, M., Takehara, T., Tatsumi, T., Yamaguchi, S., Sakamori, R., Hiramatsu, N., Kanto, T., Ohkawa, K., Hayashi, N
  • Journal Title: Immunology 120 Pages: 73-82
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Natural killer cell-mediated ablation of metastatic liver tumors by hydrodynamic injection of IFNα gene to mice (2007)
  • Author(s): Takehara, T., Uemura, A., Tatsumi, T., Suzuki, T., Kimura, R., Shiotani, A., Ohkawa, K., Kanto, T., Hiramatsu, N., Hayashi, N
  • Journal Title: Int J Cancer 120 Pages: 1252-1260
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Natural killer cell-mediated ablation of metastatic liver tumors by hydrodynamic injection of IFNα gene to mice. (2007)
  • Author(s): Takehara T, Uemura A, et. al.
  • Journal Title: International Journal of Cancer 120 Pages: 1252-1260
  • Peer Reviewed
• [Journal Article] Natural killer cell and hepatic cell interaction via NKG2A leads to dendritic cell-mediated induction of CD4+CD25+ T cells with PD-1-dependent regulatory activities. (2007)
  • Author(s): Jinushi M, Takehara T, et. al.
  • Journal Title: Immunology 120 Pages: 73-82
  • Peer Reviewed
• [Journal Article] Impahed ability of interferon-alpha-primed dendritic cells to stimulate Th1-type CD4 T-cell response in chronic hepatitis C virus infection. (2007)
  • Author(s): Miyatake H, Kanto T, et. al.
  • Journal Title: J Viral Hepat 14 Pages: 404-412
  • Peer Reviewed
• [Journal Article] Injection of IL-12 gene-transduced dendritic cells into mouse liver tumor lesions activates both innate and acquired immunity. (2007)
  • Author(s): Tatsumi T, Takehara T, et. al.
  • Journal Title: Gene Ther 14 Pages: 863-871
  • Peer Reviewed
• [Journal Article] Involvement of dendlitic cell frequency and function in virological relapse in pegylated interferon-alpha and ribavirin therapy for chronic hepatitis Cpatients. (2007)
  • Author(s): Itose I, Kanto T, et. al.
  • Journal Title: J Med Virol 79 Pages: 511-521
  • Peer Reviewed
• [Journal Article] Immunotherapy of murine colon cancer using receptor tyrosine kinase EphA2-derived peptide-pulsed dendritic cell vaccines. (2007)
  • Author(s): Yamaguchi S, Tatsumi T, et. al.
  • Journal Title: Cancer 110 Pages: 1469-1477
  • Peer Reviewed
• [Journal Article] Quick generation of fully mature dendritic cells from monocytes with OK432, low-doseprostanoid and interferon-α as potent immune enhancers. (2006)
  • Author(s): Sakakibara M, Takehara T, et al.
  • Journal Title: Journal of Immunotherapy 29 Pages: 67-77
• [Journal Article] Reduced expression and functional impairment of Toll-like receptor 2 on dendritic cells in chronic hepatitis C virus infection. (2006)
  • Author(s): Yakushijin T, Takehara T, et al.
  • Journal Title: Hepatology Research 35 Pages: 185-189
  • NAID: 10020405278
• [Journal Article] Enhanced ability of peripheral invariant natural killer T cells to produce IL-13 in chronic hepatitis C virus infection. (2006)
  • Author(s): Inoue M, Takehara T, et al.
  • Journal Title: Journal of Hepatology 45 Pages: 190-196
• [Journal Article] Suppressive effect on hepatocyte differentiation of hepatitis C virus core protein. (2006)
  • Author(s): Hosui A, Takehara T, et al.
  • Journal Title: Biochemical and Biophysical Research Communications 346 Pages: 1125-1130
• [Journal Article] Should aged patients with chronic hepatitis C be treated with interferon and ribavirin combination therapy? (2006)
  • Author(s): Hiramatsu N, Takehara T, et al.
  • Journal Title: Hepatology Research 35 Pages: 185-189
  • NAID: 10018774942
• [Journal Article] Early decline of hemoglobin correlates with progression of ribavirin-induced hemolytic anemia during interferon plus ribavirin combination therapy in patients with chronic hepatitis C. (2006)
  • Author(s): Oze T, Takehara T, et al.
  • Journal Title: Journal of Gastroenterology 41 Pages: 862-872
  • NAID: 10020626268
• [Presentation] Regulation of the NKG2D immunoreceptor by soluble MICA during transcatheter arterial embolization for hepatocellular carcinoma. (2007)
  • Author(s): Kohga K, Takehara T, et. al.
  • Organizer: 58th Annual Meeting, The American Association for the Study of Liver Diseases
  • Place of Presentation: Boston(USA)
  • Description: 「研究成果報告書概要(和文)」より
• [Presentation] Regulation of the NKG2D immunoreceptor by soluble MICA during transcatheter arterial embolization for hepatocellular carcinoma (2007)
  • Author(s): Kohga, K., Takehara, T., Hikita, H., Sasakawa, A., Uemura, A., Sakamori, R., Yamaguchi, S., Tatsumi, T., Ohkawa, K., Kanto, T., Hiramatsu, N., Katayama, K., Kato, M., Hayashi, N
  • Organizer: The American Association for the Study of Liver Diseases The 58th Annual Meeting AASLD
  • Place of Presentation: Hynes Convention Center, Boston, MA, USA
  • Description: 「研究成果報告書概要(欧文)」より
• [Presentation] Regulation of the NKG2D immunoreceptor by soluble MICA during tran scatheter arterial embolization for hepatocellular, carcinoma. (2007)
  • Author(s): Kohga K, Takehara T, et. al.
  • Organizer: 58th Annual Meeting, The American Association for the Study of Liver Diseases
  • Place of Presentation: Boston (USA)
• [Book] Innate immunity in type C hepatitis. Hepatitis C virus disease. (2008)
  • Author(s): Takehara T, Hayashi N
  • Publisher: Immunobiology and clinical applications. Edited by Emilio jirillo. Springer, USA.
  • Description: 「研究成果報告書概要(和文)」より
• [Book] Innate immunity in type C hepatitis. Hepatitis C virus disease. (2008)
  • Author(s): Takehara T, Hayashi N
  • Publisher: Immunobiology and clinical applications. Edited by Emilio Jirillo. Springer, USA.