Elucidation and development of control method of the immune escape mechanism of circulating tumor cells of hepatocellular carcinoma

• Project/Area Number: 18K08706
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 55020:Digestive surgery-related
• Research Institution: Hiroshima University
• Principal Investigator: Kobayashi Tsuyoshi 広島大学, 医系科学研究科(医), 准教授 (50528007)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Project Status: Completed (Fiscal Year 2020)
• Budget Amount: ¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000); Fiscal Year 2020: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000); Fiscal Year 2019: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2018: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
• Keywords: 肝細胞癌 / 循環腫瘍細胞 / 遺伝子多型 / 免疫逃避機構 / SIRPα / CD47 / 免疫逃避

Outline of Final Research Achievements

The purpose of this study was to elucidate and develop a method for releasing immune escape mechanism in the macrophage immune checkpoint system using single-cell analysis of Glypican-3 (GPC3) -positive circulating tumor cells (CTC) specific for hepatocellular carcinoma (HCC).
In a study of 132 HCC patients, GPC3-CTC, AFP, DCP, and multiple tumors were independent risk factors for postoperative recurrence. In the SIRPα IgV domain variant analysis of 255 HCC patients, V1 variant was significantly poor in both recurrence-free survival rate and overall survival rate. The effect of CD47 expression on GPC3-CTC on prognosis was not significant. In the analysis of PD-1 gene polymorphism PD-1.1 in 321 HCC patients, the GG allele had a significantly higher rate of extrahepatic recurrence.

Academic Significance and Societal Importance of the Research Achievements

HCCの再発予防療法開発が困難な理由として、heterogeneityが極めて大きいことが考えられるが、HCC特異的なGPC3-CTCを標的とした機能解析や治療戦略はheterogeneityを克服できる可能性を秘めている。マクロファージCD47-SIRPαシグナルは新たな免疫チェックポイント機構であり、その阻害療法が期待されている。CD47-SIRPαシグナルにおける免疫回避機構解明とその制御法の開発は、画期的な治療手段となる可能性がある。

Research Products

• [Journal Article] PD1 gene polymorphism is associated with a poor prognosis in hepatocellular carcinoma following liver resection, cohort study. (2020)
  • Author(s): Yamamoto M, Kobayashi T, Mashima H, Miki D, Kuroda S, Hamaoka M, Aikata H, Chayama K, Ohdan H.
  • Journal Title: Int J Surg. Volume: 80 Pages: 84-90
  • DOI: 10.1016/j.ijsu.2020.05.007
  • NAID: 120007168956
  • Peer Reviewed
• [Journal Article] Impact of postoperative bile leakage on long‐term outcome in patients following liver resection for hepatocellular carcinoma (2020)
  • Author(s): Yamamoto Masateru、Kobayashi Tsuyoshi、Kuroda Shintaro、Hamaoka Michinori、Honmyo Naruhiko、Yamaguchi Megumi、Takei Daisuke、Ohdan Hideki
  • Journal Title: Journal of Hepato-Biliary-Pancreatic Sciences Volume: 27 Issue: 12 Pages: 931-941
  • DOI: 10.1002/jhbp.750
  • Peer Reviewed
• [Journal Article] Treatment outcomes after splenectomy with gastric devascularization or balloon-occluded retrograde transvenous obliteration for gastric varices: a propensity score-weighted analysis from a single institution (2020)
  • Author(s): Oshita Ko、Ohira Masahiro、Honmyo Naruhiko、Kobayashi Tsuyoshi、Murakami Eisuke、Aikata Hiroshi、Baba Yasutaka、Kawano Reo、Awai Kazuo、Chayama Kazuaki、Ohdan Hideki
  • Journal Title: Journal of Gastroenterology Volume: 55 Issue: 9 Pages: 877-887
  • DOI: 10.1007/s00535-020-01693-9
  • Peer Reviewed
• [Journal Article] Antithrombin attenuates the progression of hepatocellular carcinoma by regulating neutrophil/interleukin‐8 signaling (2020)
  • Author(s): Okimoto Sho、Tashiro Hirotaka、Iwako Hiroshi、Kuroda Shintaro、Kobayashi Tsuyoshi、Hinoi Takao、Ohdan Hideki
  • Journal Title: Hepatology Research Volume: 50 Issue: 11 Pages: 1284-1296
  • DOI: 10.1111/hepr.13558
  • Peer Reviewed
• [Journal Article] Preoperative PET-CT is useful for predicting recurrent extrahepatic metastasis of hepatocellular carcinoma after resection. (2020)
  • Author(s): Morio K, Kawaoka T, Aikata H, Namba M, Uchikawa S, Kodama K, Ohya K, Fujino H, Nakahara T, Murakami E, Yamauchi M, Tsuge M, Hiramatsu A, Imamura M, Nakamura Y, Akagi M, Awai K, Kobayashi T, Ohdan H, Chayama K.
  • Journal Title: Eur J Radiol. Volume: 124 Pages: 108828-108828
  • DOI: 10.1016/j.ejrad.2020.108828
  • NAID: 120007097014
  • Peer Reviewed / Open Access
• [Journal Article] Impact of systematic segmentectomy for small hepatocellular carcinoma (2020)
  • Author(s): Kaibori Masaki、Yoshii Kengo、Hasegawa Kiyoshi、Ariizumi Shunichi、Kobayashi Tsuyoshi、Kamiyama Toshiya、Kudo Atsushi、Yamaue Hiroki、Kokudo Norihiro、Yamamoto Masakazu
  • Journal Title: Journal of Hepato-Biliary-Pancreatic Sciences Volume: 27 Issue: 6 Pages: 331-341
  • DOI: 10.1002/jhbp.720
  • Peer Reviewed
• [Journal Article] Clinical significance of glypican-3-positive circulating tumor cells of hepatocellular carcinoma patients: A prospective study. (2019)
  • Author(s): Hamaoka M, Kobayashi T, Tanaka Y, Mashima H, Ohdan H.
  • Journal Title: PLoS One Volume: 14 Issue: 5 Pages: e0217586-e0217586
  • DOI: 10.1371/journal.pone.0217586
  • Peer Reviewed
• [Journal Article] Comparison of new prognostic systems for patients with resectable hepatocellular carcinoma: Albumin-Bilirubin grade and Albumin-Indocyanine Green Evaluation grade. (2019)
  • Author(s): Honmyo N, Kobayashi T, Hamaoka M, Kohashi T, Abe T, Oishi K, Tazawa H, Imaoka Y, Akita T, Tanaka J, Ohdan H
  • Journal Title: Hepatol Res Volume: 49 Issue: 10 Pages: 1218-1226
  • DOI: 10.1111/hepr.13393
  • Peer Reviewed
• [Journal Article] Antithrombin Insufficiency Promotes Susceptibility to Liver Tumorigenesis (2019)
  • Author(s): Iwako H, Tashiro H, Okimoto S, Yamaguchi M, Abe T, Kuroda S, Kobayashi T, Ohdan H
  • Journal Title: J Surg Res Volume: 236 Pages: 198-208
  • DOI: 10.1016/j.jss.2018.11.026
  • Peer Reviewed
• [Journal Article] Verification of inflammation-based prognostic marker as a prognostic indicator in hepatocellular carcinoma (2019)
  • Author(s): Yamamoto M, Kobayashi T, Kuroda S, Hamaoka M, Okimoto S, Honmyo N, Yamaguchi M, Ohdan H
  • Journal Title: Ann Gastroenterol Surg Volume: 3 Issue: 6 Pages: 667-675
  • DOI: 10.1002/ags3.12286
  • Peer Reviewed
• [Journal Article] Influence of donor liver telomere and G-tail on clinical outcome after living donor liver transplantation. (2019)
  • Author(s): Liu B, Anno K, Kobayashi T, Piao J, Tahara H, Ohdan H.
  • Journal Title: PloS one Volume: 14 Issue: 3 Pages: e0213462-e0213462
  • DOI: 10.1371/journal.pone.0213462
  • Peer Reviewed / Open Access
• [Journal Article] Prognostic factors in patients with recurrent intrahepatic cholangiocarcinoma after curative resection: A retrospective cohort study. (2018)
  • Author(s): Ohira M, Kobayashi T, Hashimoto M, Tazawa H, Abe T, Oshita A, et al.
  • Journal Title: Int J Surg Volume: 54 Pages: 156-62
  • DOI: 10.1016/j.ijsu.2018.04.058
  • Peer Reviewed
• [Presentation] 循環腫瘍細胞からみた肝癌の外科治療戦略 (2020)
  • Author(s): 小林 剛, 山本 将輝, 大段 秀樹
  • Organizer: JDDW2020
• [Presentation] 肝癌外科治療後の再発予防に向けた取り組み (2020)
  • Author(s): Author：小林 剛, 大平 真裕, 山本 将輝, 竹井 大祐, 真島 宏聡, 濱岡 道則, 橋本 昌和, 谷峰 直樹, 黒田 慎太郎, 田原 裕之, 井手 健太郎, 田中 友加, 大段 秀樹
  • Organizer: 第79回日本癌学会総会
• [Presentation] Significance of anatomical liver resection for intrahepatic recurrence of hepatocellular carcinoma (2019)
  • Author(s): 小林剛,真島宏聡,山本将輝,本明慈彦,山口恵,沖本将,濵岡道則,黒田慎太郎,大段秀樹
  • Organizer: 第31回日本肝胆膵外科学会・学術集会
• [Presentation] 肝細胞癌術後肝内再発に対する再切除の意義と安全性 (2019)
  • Author(s): 小林剛,真島宏聡,黒田慎太郎,井手健太郎,大平真裕,田原裕之,橋本慎二,濵岡道則,大段秀樹
  • Organizer: 第74回日本消化器外科学会
• [Presentation] 高齢者の小肝細胞癌に対する治療選択 (2019)
  • Author(s): 小林剛,黒田慎太郎,大段秀樹
  • Organizer: JDDW2019
• [Presentation] リキッドバイオプシーとしての肝癌循環腫瘍細胞 (2018)
  • Author(s): 小林 剛、浜岡道則、真島宏聡、沖本将、本明慈彦、山口恵美、清水誠一、黒田慎太郎、田原裕之、大平真裕、井手健太郎、大段秀樹
  • Organizer: 第118回日本外科学会定期学術集会
• [Presentation] 肝細胞癌切除例におけるGlypican3陽性循環腫瘍細胞の臨床的意義 (2018)
  • Author(s): 小林 剛、濵岡道則、大段秀樹
  • Organizer: ＪＤＤＷ2018