Microenvironment in hepatocellular carcinoma

• Project/Area Number: 24390320
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Partial Multi-year Fund
• Section: 一般
• Research Field: Digestive surgery
• Research Institution: Kyushu University
• Principal Investigator: SHIRABE Ken 九州大学, 医学(系)研究科(研究院), 准教授 (70264025)
• Co-Investigator(Kenkyū-buntansha): TAKENOYAMA Mitsuhiro 九州がんセンター臨床研究センター, その他部局等, 呼吸器腫瘍科科長 (10309966) ; SOEJIMA Yuji 九州大学, 医学研究院, 共同研究員 (30325526) ; YONEMITSU Yoshikazu 九州大学, 薬学研究院, 教授 (40315065) ; MAEHARA Yoshihiko (AISHIMA Shinichi) 九州大学, 医学研究院, 教授 (80165662) ; YOSHIZUMI Tomoharu 九州大学, 大学病院, 講師 (80363373) ; IKEGAMI Toru 九州大学, 大学病院, 助教 (80432938) ; OKANO Shinji 九州大学, 医学研究院, 准教授 (10380429) ; 相島 慎一 佐賀大学, 医学部, 教授 (70346774)
• Project Period (FY): 2012-04-01 – 2015-03-31
• Project Status: Completed (Fiscal Year 2014)
• Budget Amount: ¥18,590,000 (Direct Cost: ¥14,300,000、Indirect Cost: ¥4,290,000); Fiscal Year 2014: ¥5,330,000 (Direct Cost: ¥4,100,000、Indirect Cost: ¥1,230,000); Fiscal Year 2013: ¥3,510,000 (Direct Cost: ¥2,700,000、Indirect Cost: ¥810,000); Fiscal Year 2012: ¥9,750,000 (Direct Cost: ¥7,500,000、Indirect Cost: ¥2,250,000)
• Keywords: 肝臓外科学 / PD-L1 / HLA I / 肝細胞癌 / HLA I / 腫瘍関連マクロファージ / STAT3 / Il-17

Outline of Final Research Achievements

We have shown tumor associated macrophage (TAM) accelerates malignant potential in hepatocellular carcinoma (HCC). Expression of programmed cell death 1 (PD L1) and human leukocyte antigen class I (HLA I) were examined in HCC in the resected specimens. PD-L1 expression was significantly correlated with TAM accumulation and the patients with PD-L1 negative and HLA I positive HCC had favorable prognosis. This suggests that blockade of PD-L1 and PD-1 pathway might be effective therapeutic strategy. In our recent study, PD-L1 expression was significantly correlated with immune suppression and epithelial mesenchymal transition of cancer cells in pancreatic cancer.
To clarify the relationship among IL-17, TAM, PD-1, and PD-L1, subcutaneous tumor model, using IFN sensitive mouse HCC cell line, was established. This model was planned to be applied to IL17KO、and IFN-γKO mouse. Nevertheless, IL17 expression was unstable and we have gotten new KO mouse and we have continued this experiment.

Research Products

• [Journal Article] Prognostic impact of programmed cell death 1 ligand 1 expression in human leukocyte antigen class I-positive hepatocellular carcinoma after curative hepatectomy. (2014)
  • Author(s): Umemoto Y, Okano S, Matsumoto Y, Nakagawara H, Matono R, Yoshiya S, Yamashita YI, Yoshizumi T, Ikegami T, Soejima Y, Harada M, Aishima S, Oda Y, Shirabe K, Maehara Y.
  • Journal Title: J Gastroenterol. Volume: not determined Issue: 1 Pages: 65-75
  • DOI: 10.1007/s00535-014-0933-3
  • Peer Reviewed / Open Access
• [Journal Article] Prognostic factors affecting survival at recurrence of hepatocellular carcinoma after living-donor liver transplantation: with special reference to neutrophil/lymphocyte ratio. (2013)
  • Author(s): Harimoto N, Shirabe K, Nakagawara H, Toshima T, Yamashita Y, Ikegami T, Yoshizumi T, Soejima Y, Ikeda T, Maehara Y.
  • Journal Title: Transplantation Volume: 96(11) Issue: 11 Pages: 1008-12
  • DOI: 10.1097/tp.0b013e3182a53f2b
  • Peer Reviewed
• [Journal Article] Tumor-Associated Macrophage Promotes Tumor Progression via STAT3 Signaling in Hepatocellular Carcinoma. (2013)
  • Author(s): 119. Mano Y, Aishima S, Fujita N, Tanaka Y, Kubo Y, Motomura T, Taketomi A, Shirabe K, Maehara Y, Oda Y.
  • Journal Title: Pathobiology. Volume: 80 Issue: 3 Pages: 146-154
  • DOI: 10.1159/000346196
  • Peer Reviewed
• [Journal Article] Impact of tumor size, number of tumors and neutrophil-to-lymphocyte ratio in liver transplantation for recurrent hepatocellular carcinoma. (2013)
  • Author(s): Yoshizumi T, Ikegami T, Yoshiya S, Motomura T, Mano Y, Muto J, Ikeda T, Soejima Y, Shirabe K, Maehara Y.
  • Journal Title: Hepatol Res. Volume: 43 Issue: 7 Pages: 709-16
  • DOI: 10.1111/hepr.12016
  • Peer Reviewed
• [Journal Article] Neutrophil-lymphocyte ratio reflects hepatocellular carcinoma recurrence after liver transplantation via inflammatory microenvironment. (2013)
  • Author(s): Motomura T, Yoshizumi T, et al
  • Journal Title: Journal of Hepatology Volume: 58 Issue: 1 Pages: 58-64
  • DOI: 10.1016/j.jhep.2012.08.017
  • Peer Reviewed
• [Presentation] 膵癌における間葉系形質の獲得とPD-L１の発現に関する臨床病理学的検討 (2015)
  • Author(s): 今井大祐、調 憲ほか
  • Organizer: 第36回癌免疫外科研究会
  • Place of Presentation: 奄美観光ホテル
  • Year and Date: 2015-05-14 – 2015-05-15
• [Presentation] 進行肝癌における炎症マーカーの意義 (2014)
  • Author(s): 調 憲
  • Organizer: 第50回日本肝癌研究会
  • Place of Presentation: 京都国際会議場
  • Year and Date: 2014-06-05 – 2014-06-06
  • Invited
• [Presentation] 肝細胞癌外科的治療における術前末梢血好中球リンパ球比(Neutrophil/lymphocyte ratio : NLR)の意義 (2013)
  • Author(s): 間野洋平
  • Organizer: 第113回日本外科学会定期学術集会
  • Place of Presentation: 福岡マリンメッセ
  • Year and Date: 2013-04-11