Impact of anti-tumor immune responses to microenvironment in hepatocellular carcinoma

• Project/Area Number: 17K15934
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Gastroenterology
• Research Institution: Kanazawa University
• Principal Investigator: Takeshi Terashima 金沢大学, 先進予防医学研究センター, 特任准教授 (90775305)
• Project Period (FY): 2017-04-01 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥4,030,000 (Direct Cost: ¥3,100,000、Indirect Cost: ¥930,000); Fiscal Year 2019: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2018: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2017: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000)
• Keywords: 抗腫瘍免疫 / 肝細胞癌 / 腫瘍浸潤リンパ球 / 個別化医療 / 抗腫瘍免疫反応

Outline of Final Research Achievements

The aim of this study was to immunohistochemically evaluate the surface antigen on tumor infiltrating lymphocytes in hepatocellular carcinoma. We clarified some surface antigen expression on tumor infiltrating lymphocytes into the interior of tumor was a predictive marker for anti-tumor effect of treatment and patients’ outcome.

Academic Significance and Societal Importance of the Research Achievements

これまで、肝細胞癌に対する治療方針は主に、大きさや転移の有無などの腫瘍の拡がり（病期）や肝臓の予備能力によって決定されてきた。本研究で、切除後の経過が異なることを明らかにしたことにより、今後は、腫瘍に浸潤した免疫担当細胞の数や種類という、患者さんが持っている抗腫瘍免疫の情報も参考に加えることで、それぞれの患者さんに最適な治療（個別化医療）を提供できる可能性があると考えられる。

Research Products

• [Journal Article] Comparative analysis of liver functional reserve during lenvatinib and sorafenib for advanced hepatocellular carcinoma. (2020)
  • Author(s): Terashima T, Yamashita T, Takata N, Toyama T, Shimakami T, Takatori H, Arai K, Kawaguchi K, Kitamura K, Yamashita T, Sakai Y, Mizukoshi E, Honda M, Kaneko S.
  • Journal Title: Hepatology Research Volume: - Issue: 7 Pages: 871-884
  • DOI: 10.1111/hepr.13505
  • Peer Reviewed / Open Access
• [Journal Article] IL-28B variant as a predictor in patients with advanced hepatocellular carcinoma treated with hepatic arteiral infusion chemotherapy. (2020)
  • Author(s): Terashima T, Honda M, Toyama T, Shimakami T, Shimizu R, Takatori H, Arai K, Kawaguchi K, Kitamura K, Yamashita T, Sakai Y, Yamashita T, Mizukoshi E, Kaneko S.
  • Journal Title: Journal of Gastroenterology and Hepatology Volume: - Issue: 10 Pages: 1813-1820
  • DOI: 10.1111/jgh.15035
  • Peer Reviewed / Open Access
• [Journal Article] Inactivation of Transcriptional Repressor Capicua Confers Sorafenib Resistance in Human Hepatocellular Carcinoma (2020)
  • Author(s): Hashiba Tomomi、Yamashita Taro、et al
  • Journal Title: Cellular and Molecular Gastroenterology and Hepatology Volume: 20 Issue: 2 Pages: 30039-4
  • DOI: 10.1016/j.jcmgh.2020.02.009
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] A novel α-fetoprotein-derived helper T-lymphocyte epitope with strong immunogenicity in patients with hepatocellular carcinoma (2020)
  • Author(s): Tamai Toshikatsu、Mizukoshi Eishiro、Kumagai Masashi、Terashima Takeshi、Iida Noriho、Kitahara Masaaki、Shimakami Tetsuro、Kitamura Kazuya、Arai Kuniaki、Yamashita Taro、Sakai Yoshio、Yamashita Tatsuya、Honda Masao、Fushimi Kazumi、Kaneko Shuichi
  • Journal Title: Scientific Reports Volume: 10 Issue: 1 Pages: 4021-4021
  • DOI: 10.1038/s41598-020-60843-4
  • Peer Reviewed / Open Access
• [Journal Article] Fatty acid-driven modifications in T-cell profiles in non-alcoholic fatty liver disease patients. (2020)
  • Author(s): T Seike, E Mizukoshi, K Yamada, H Okada, M Kitahara, T Yamashita, K Arai, T Terashima, N Iida, K Fushimi, T Yamashita, Y Sakai, M Honda, K Harada, S Kaneko.
  • Journal Title: J Gastroenterol Volume: - Issue: 7 Pages: 701-711
  • DOI: 10.1007/s00535-020-01679-7
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Danaparoid sodium-based anticoagulation therapy for portal vein thrombosis in cirrhosis patients (2019)
  • Author(s): Hayashi T、Takatori H、Horii R、Nio K、Terashima T、Iida N、Kitahara M、Shimakami T、Arai K、Kitamura K、Kawaguchi K、Yamashita T、Sakai Y、Yamashita T、Mizukoshi E、Honda M、Toyama T、Okumura K、Kozaka K、Kaneko S
  • Journal Title: BMC Gastroenterology Volume: 19 Issue: 1 Pages: 217-217
  • DOI: 10.1186/s12876-019-1140-8
  • Peer Reviewed / Open Access
• [Journal Article] Germline mutations in cancer-predisposition genes in patients with biliary tract cancer. (2019)
  • Author(s): Terashima T, Umemoto K, Takahashi H, Hosoi H, Takai E, Kondo S, Sakamoto Y, Mitsunaga S, Ohno I, Hashimoto Y, Sasaki M, Ikeda M, Shimada K, Kaneko S, Yachida S, Sugano K, Okusaka T, Morizane C.
  • Journal Title: Oncotarget Volume: 10 Issue: 57 Pages: 5949-5957
  • DOI: 10.18632/oncotarget.27224
  • Peer Reviewed
• [Journal Article] Characteristics of impaired dendritic cell function in patients with hepatitis B virus infection. (2019)
  • Author(s): Yonejima A, Mizukoshi E, Tamai T, Nakagawa H, Kitahara M, Yamashita T, Arai K, Terashima T, Iida N, Fushimi K, Okada H, Yamashita T, Sakai Y, Honda M, Kaneko S.
  • Journal Title: Hepatology Volume: 10.1002/hep Issue: 1 Pages: 30637-30637
  • DOI: 10.1002/hep.30637
  • Peer Reviewed / Open Access
• [Journal Article] Development of novel diagnostic system for pancreatic cancer, including early stages, measuring mRNA of whole blood cells (2019)
  • Author(s): Sakai Yoshio、Honda Masao、Matsui Shigeyuki、Komori Osamu、Murayama Toshinori、Fujiwara Tadami、Mizuno Masaaki、Imai Yasuhito、Yoshimura Kenichi、Nasti Alessandro、Wada Takashi、Iida Noriho、Kitahara Masaaki、Horii Rika、Toshikatsu Tamai、Nishikawa Masashi、Okafuji Hirofumi、Mizukoshi Eishiro、et al
  • Journal Title: Cancer Science Volume: 110 Issue: 4 Pages: 1364-1388
  • DOI: 10.1111/cas.13971
  • Peer Reviewed / Open Access
• [Journal Article] Biological characteristics of gene expression features in pancreatic cancer cells induced by proton and X-ray irradiation. (2018)
  • Author(s): Fujinaga H, Sakai Y, Yamashita T, Arai K, Terashima T, Komura T, Seki A, Kawaguchi K, Nasti A, Yoshida K, Wada T, Yamamoto K, Kume K, Hasegawa T, Takata T, Honda M, Kaneko S.
  • Journal Title: Int J Radiat Biol Volume: 17 Issue: 5 Pages: 1-9
  • DOI: 10.1080/09553002.2019.1558297
  • Peer Reviewed / Open Access
• [Journal Article] Clinical characteristics of Japanese patients with epithelioid hemangioendothelioma: a multicenter retrospective study. (2018)
  • Author(s): Shiba S, Imaoka H, Shioji K, Suzuki E, Horiguchi S, Terashima T, Kojima Y, Okuno T, Sukawa Y, Tsuji K, Umemoto K, Asagi A, Todaka A, Ueno M, Ikeda M, Morizane C, Furuse J.
  • Journal Title: BMC Cancer Volume: 18 Issue: 1 Pages: 993-993
  • DOI: 10.1186/s12885-018-4934-0
  • Peer Reviewed
• [Journal Article] Treatment patterns and outcomes of unresectable pancreatic cancer patients in real-life practice: A region-wide analysis. (2018)
  • Author(s): Terashima T, Yamashita T, Sakai A, Ohta H, Hinoue Y, Toya D, Kawai H, Yonejima M, Urabe T, Noda Y, Mizukoshi E, Kaneko S.
  • Journal Title: Jpn J Clin Oncol Volume: 48 Issue: 11 Pages: 966-973
  • DOI: 10.1093/jjco/hyy132
  • Peer Reviewed
• [Journal Article] Multicenter retrospective analysis of systemic chemotherapy for unresectable combined hepatocellular and cholangiocarcinoma. (2018)
  • Author(s): Kobayashi S, Terashima T, Shiba S, Yoshida Y, Yamada I, Iwadou S, Horiguchi S, Takahashi H, Suzuki E, Moriguchi M, Tsuji K, Otsuka T, Asagi A, Kojima Y, Takada R, Morizane C, Mizuno N, Ikeda M, Ueno M, Furuse J.
  • Journal Title: Cancer Sci Volume: 109 Issue: 8 Pages: 2549-2557
  • DOI: 10.1111/cas.13656
  • Peer Reviewed
• [Journal Article] Immune responses of human T lymphocytes to novel hepatitis B virus-derived peptides (2018)
  • Author(s): Yamamiya D, Mizukoshi E, Kaji K, Terashima T, Kitahara M, Yamashita T, Arai K, Fushimi K, Honda M, Kaneko S.
  • Journal Title: PLoS one Volume: 13 Issue: 6 Pages: e0198264-e0198264
  • DOI: 10.1371/journal.pone.0198264
  • Peer Reviewed / Open Access
• [Journal Article] Analysis of the liver functional reserve of patients with advanced hepatocellular carcinoma undergoing sorafenib treatment: Prospects for regorafenib therapy. (2018)
  • Author(s): Terashima T, Yamashita T, Sunagozaka H, Arai K, Kawaguchi K, Kitamura K, Yamashita T, Sakai Y, Mizukoshi E, Honda M, Kaneko S.
  • Journal Title: Hepatol Res Volume: 48 Issue: 12 Pages: 956-966
  • DOI: 10.1111/hepr.13196
  • Peer Reviewed / Open Access
• [Journal Article] Immune responses against tumor-associated antigen-derived cytotoxic T lymphocyte epitopes in cholangiocarcinoma patients. (2018)
  • Author(s): Kida A, Mizukoshi E, Tamai T, Kitahara M, Yamashita T, Arai K, Terashima T, Iida N, Fushimi K, Kaneko S.
  • Journal Title: Liver Int Volume: 38 Issue: 11 Pages: 2040-2050
  • DOI: 10.1111/liv.13885
  • Peer Reviewed / Open Access
• [Journal Article] Immune response to human telomerase reverse transcriptase-derived helper T cell epitopes in hepatocellular carcinoma patients (2018)
  • Author(s): Kumagai Masashi、Mizukoshi Eishiro、Tamai Toshikatsu、Kitahara Masaaki、Yamashita Tatsuya、Arai Kuniaki、Terashima Takeshi、Iida Noriho、Fushimi Kazumi、Kaneko Shuichi
  • Journal Title: Liver International Volume: 印刷中 Issue: 9 Pages: 1635-1645
  • DOI: 10.1111/liv.13713
  • Peer Reviewed / Open Access
• [Journal Article] Serum Wisteria floribunda agglutinin-positive Mac-2 binding protein predicts hepatocellular carcinoma incidence and recurrence in nucleos(t)ide analogue therapy for chronic hepatitis B. (2017)
  • Author(s): Kawaguchi K, Honda M, Ohta H, Terashima T, Shimakami T, Arai K, Yamashita T, Sakai Y, Yamashita T, Mizukoshi E, Komura T, Unoura M, Kaneko S
  • Journal Title: J Gastroenterol Volume: ePub ahead Issue: 6 Pages: 740-751
  • DOI: 10.1007/s00535-017-1386-2
  • Peer Reviewed / Open Access
• [Journal Article] Familial pancreatic cancer: Concept, management and issues (2017)
  • Author(s): Matsubayashi Hiroyuki、Takaori Kyoichi、Morizane Chigusa、Maguchi Hiroyuki、Mizuma Masamichi、Takahashi Hideaki、Wada Keita、Hosoi Hiroko、Yachida Shinichi、Suzuki Masami、Usui Risa、Furukawa Toru、Furuse Junji、Sato Takamitsu、Ueno Makoto、Kiyozumi Yoshimi、Hijioka Susumu、Mizuno Nobumasa、Terashima Takeshi、et al.
  • Journal Title: World Journal of Gastroenterology Volume: 23 Issue: 6 Pages: 935-935
  • DOI: 10.3748/wjg.v23.i6.935
  • NAID: 120006355742
  • Peer Reviewed / Open Access
• [Journal Article] Beneficial Effect of Maintaining Hepatic Reserve during Chemotherapy on the Outcomes of Patients with Hepatocellular Carcinoma. (2017)
  • Author(s): Terashima T, Yamashita T, Arai K, Kawaguchi K, Kitamura K, Yamashita T, Sakai Y, Mizukoshi E, Honda M, Kaneko S.
  • Journal Title: Liver Cancer Volume: 6 Issue: 3 Pages: 236-249
  • DOI: 10.1159/000472262
  • Peer Reviewed / Open Access
• [Journal Article] Serum cytokine profiles predict survival benefits in patients with advanced hepatocellular carcinoma treated with sorafenib: a retrospective cohort study. (2017)
  • Author(s): Hayashi T, Yamashita T, Terashima T, Suda T, Okada H, Asahina Y, Hayashi T, Hara Y, Nio K, Sunagozaka H, Takatori H, Arai K, Sakai Y, Yamashita T, Mizukoshi E, Honda M, Kaneko S.
  • Journal Title: BMC Cancer Volume: 17 Issue: 1 Pages: 870-870
  • DOI: 10.1186/s12885-017-3889-x
  • Peer Reviewed / Open Access
• [Presentation] 進行肝癌新規薬物療法時代における肝動注化学療法の位置づけ (2019)
  • Author(s): 寺島健志，山下竜也，金子周一
  • Organizer: 第105回日本消化器病学会総会
• [Presentation] Immunotherapy for HCC: current status and new challenges (2019)
  • Author(s): Takeshi Terashima
  • Organizer: The 5th International Symposium on Viral Hepatitis
  • Int'l Joint Research
• [Presentation] Comparative analysis of liver functional reserve during chemotherapy (2019)
  • Author(s): 寺島健志，山下竜也，金子周一
  • Organizer: 第55回日本肝臓学会総会
• [Presentation] 複数の薬物療法が選択可能な状況下における進行肝細胞癌に対する治療戦略 (2019)
  • Author(s): 寺島健志
  • Organizer: 第20回日本肝がん分子標的治療研究会
  • Invited
• [Presentation] Comparative analysis of liver functional reserve during lenvatinib with sorafenib for advanced hepatocellular carcinoma (2019)
  • Author(s): Takeshi Terashima, Tatsuya Yamashita, Shuichi Kaneko
  • Organizer: 第17回日本臨床腫瘍学会学術集会
• [Presentation] レンバチニブ投与後に発現した肝性脳症についての検討 (2019)
  • Author(s): 寺島健志，山下竜也，高田昇，鷹取元，荒井邦明，金子周一
  • Organizer: 第26回 日本門脈圧亢進症学会総会
• [Presentation] 肝臓に病変が限局した神経内分泌腫瘍の三例 (2019)
  • Author(s): 寺島健志，山下竜也，高田昇，荒井邦明，水腰英四郎，原田憲一，金子周一
  • Organizer: 第7回日本神経内分泌腫瘍研究会学術集会
• [Presentation] Liver-related adverse events after Immune-checkpoint inhibitor (2019)
  • Author(s): Takeshi Terashima，Eishiro Mizukoshi，Shuichi Kaneko
  • Organizer: Japan Digestive Disease Week 2019
• [Presentation] 複数の薬物療法が選択可能な状況下における進行肝細胞癌に対する治療戦略 (2019)
  • Author(s): 寺島健志
  • Organizer: 第43回日本肝臓学会西部会
• [Presentation] 肝細胞癌と結腸・直腸癌に対するレゴラフェニブの初期有害事象の検討 (2018)
  • Author(s): 寺島健志、山下竜也、高田昇、堀井里和、荒井邦明、中村慶史、金子周一
  • Organizer: 第17回日本肝がん分子標的治療研究会
• [Presentation] Surrogacy of time to progression for overall survival in advanced hepatocellular carcinoma treated with systemic therapy: A systematic review and meta-analysis of randomized controlled trials (2018)
  • Author(s): Takeshi Terashima, Tatsuya Yamashita, Kuniaki Arai, Tadashi Toyama, Kazunori Kawaguchi, Kazuya Kitamura, Taro Yamashita, Yoshio Sakai, Eishiro Mizukoshi, Masao Honda, Shuichi Kaneko
  • Organizer: 2018 Gastrointestinal Cancer Symposium
  • Int'l Joint Research
• [Presentation] 根治切除不能膵癌に対する二次化学療法の進歩 (2018)
  • Author(s): 寺島健志，山下竜也，金子周一
  • Organizer: 第104回日本消化器病学会総会
• [Presentation] New development of lenvatinib for treatment of advanced hepatocellular carcinoma (2018)
  • Author(s): Takeshi Terashima
  • Organizer: The Asian Pacific Association for the Study of the Liver Single Topic Conference on HCC
  • Int'l Joint Research / Invited
• [Presentation] 肝細胞癌局所における免疫細胞浸潤と再発時治療効果との関連についての検討 (2018)
  • Author(s): 寺島健志，水腰英四郎，金子周一
  • Organizer: 第54回日本肝臓学会総会
• [Presentation] 進行肝細胞癌患者における全生存期間に対する無増悪生存期間の意義 (2018)
  • Author(s): 寺島健志，山下竜也，金子周一
  • Organizer: 第54回日本肝癌研究会
• [Presentation] 膵癌化学療法患者における糖尿病合併の影響と糖尿病治療効果の検討 (2018)
  • Author(s): 寺島健志，山下竜也，鷹取元，島孝佑，金子周一
  • Organizer: 第49回日本膵臓学会大会
• [Presentation] Surrogacy of time to progression for overall survival in advanced hepatocellular carcinoma treated with systemic therapy: A systematic review and meta-analysis of randomized controlled trials (2018)
  • Author(s): Takeshi Terashima, Tatsuya Yamashita, Shuichi Kaneko
  • Organizer: 第16回日本臨床腫瘍学会学術集会
• [Presentation] 免疫チェックポイント阻害薬投与後に発現する肝障害の検討 (2018)
  • Author(s): 寺島健志、大坪公士郎、金子周一
  • Organizer: JDDW2018
• [Presentation] Impact of tumor infiltrating lymphocytes on anti-tumor effect and patient outcome in recurrent hepatocellular carcinoma (2018)
  • Author(s): Takeshi Terashima, Eishiro Mizukoshi, Tatsuya Yamashita, Shuichi Kaneko
  • Organizer: AASLD 2018
  • Int'l Joint Research
• [Presentation] Surrogacy of time to progression for overall survival in advanced hepatocellular carcinoma (2018)
  • Author(s): Takeshi Terashima, Tatsuya Yamashita, Kuniaki Arai, Tadashi Toyama, Kazunori Kawaguchi, Kazuya Kitamura,Taro Yamashita, Yoshio Sakai, Eishiro Mizukoshi, Masao Honda, Shuichi Kaneko
  • Organizer: Gastrointestinal Cancers Symposium 2018
  • Int'l Joint Research
• [Presentation] 高齢者進行肝細胞癌患者に対する肝動注化学療法の検討 (2017)
  • Author(s): 寺島健志、山下竜也、金子周一
  • Organizer: 第53回日本肝臓学会総会
• [Presentation] 肝動注化学療法により完全奏効が得られた進行肝細胞癌患者の検討 (2017)
  • Author(s): 寺島健志、山下竜也、吉田亮太、荒井邦明、水腰英四郎、金子周一
  • Organizer: 第103回日本消化器病学会総会
• [Presentation] 進行肝細胞癌患者に対するソラフェニブ治療後に肝内病変を標的とした治療の有用性 (2017)
  • Author(s): 寺島健志、山下竜也、金子周一
  • Organizer: 第16回日本肝がん分子標的治療研究会
• [Presentation] 肝予備能の推移から検討した進行肝細胞癌に対するソラフェニブと肝動注化学療法の選択 (2017)
  • Author(s): 寺島健志、山下竜也、高田昇、堀井里和、砂子阪肇、荒井邦明、金子周一
  • Organizer: 第53回日本肝癌研究会
• [Presentation] ペグフィルグラスチム併用FOLFIRINOX療法における治療強度の検討 (2017)
  • Author(s): 寺島健志，山下竜也，岡藤啓史，林智之，鷹取元，北村和哉，水腰英四郎，金子周一
  • Organizer: 第48回日本膵臓学会大会
• [Presentation] Multicenter retrospective study of systemic chemotherapy for unresectable combined hepatocellular and cholangiocarcioma (2017)
  • Author(s): 寺島健志，小林智，柴知史，吉田幸生，山田育弘，岩堂昭太，堀口繁，高橋秀明，上野誠，古瀬純司
  • Organizer: 第15回日本臨床腫瘍学会学術集会
• [Presentation] Significance of conversion therapy for responders to hepatic arterial infusion chemotherapy (2017)
  • Author(s): Takeshi Terashima, Tatsuya Yamashita, Ryota Yoshida, Hajime Takatori, Shuichi Kaneko
  • Organizer: 第15回日本臨床腫瘍学会学術集会
• [Presentation] 治験分担医師からのメッセージ～PMDAでの新薬審査経験を経て治験分担医師としてCRCに期待すること～ (2017)
  • Author(s): 寺島健志
  • Organizer: 第17回CRCと臨床試験のあり方を考える会議
  • Invited
• [Presentation] Characteristics, treatment and outcome for patients with unresectable pancreatic cancer under clinical practice- A region-wide Japanese multicenter survey (2017)
  • Author(s): Takeshi Terashima, Tatsuya Yamashita, Shuichi Kaneko
  • Organizer: JDDW 2018
• [Presentation] Hepatic reserve and the other conditions for regorafenib as second-line treatment in patients with advanced hepatocellular carcinoma following first-line therapy with sorafenib in Japanese practical setting (2017)
  • Author(s): Takeshi Terashima, Tatsuya Yamashita, Kuniaki Arai, Shuichi Kaneko
  • Organizer: ESMO Asia 2017 Congress
  • Int'l Joint Research
• [Presentation] 肝細胞癌と結腸・直腸癌に対するレゴラフェニブの初期有害事象の検討 (2017)
  • Author(s): 寺島 健志，山下 竜也，高田 昇，堀井里和，荒井 邦明，中村 慶史，金子 周一
  • Organizer: 第17回日本肝がん分子標的治療研究会