Functional analysis of immune checkpoint molecules and the new therapeutic development by targeting their regulation

• Project/Area Number: 16K10508
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Digestive surgery
• Research Institution: Kagoshima University
• Principal Investigator: Arigami Takaaki 鹿児島大学, 医歯学総合研究科, 特任准教授 (40527058)
• Co-Investigator(Kenkyū-buntansha): 大久保 啓史 鹿児島大学, 附属病院, 医員 (40772223) ; 上之園 芳一 鹿児島大学, 医歯学総合研究科, 客員研究員 (60398279) ; 夏越 祥次 鹿児島大学, 医歯学域医学系, 教授 (70237577)
• Project Period (FY): 2016-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000); Fiscal Year 2018: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000); Fiscal Year 2017: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2016: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
• Keywords: 免疫チェックポイント阻害剤 / 免疫逃避機構 / T細胞性免疫応答 / B7 ligand family / バイオマーカー / 免疫チェックポイント分子 / 免疫療法 / 癌免疫機構 / PD-L1 / HHLA2 / 胃癌 / 好中球リンパ球比 / Fibrinogen

Outline of Final Research Achievements

This study assessed the clinical significance of PD-L1 and HHLA2 mRNA expressions in blood specimens obtained from patients with gastric cancer. PD-L1 and HHLA2 mRNA expressions were evaluated by quantitative reverse transcription-polymerase chain reaction. PD-L1 expression correlated positively with depth of tumor invasion, distant metastasis, and stage. Patients with high PD-L1 expression displayed significantly poorer prognosis. On the other hand, HHLA2 expression was inversely correlated with depth of tumor invasion, distant metastasis, and stage. Patients with low HHLA2 expression showed significantly poorer prognosis. Consequently, this study suggests that PD-L1 and HHLA2 have inhibitory and facilitatory signals for T cell-mediated immune response, respectively.

Academic Significance and Societal Importance of the Research Achievements

癌免疫療法の標的となっている免疫チェックポイント分子は未だに限定的であるが、新規免疫チェックポイント分子のHHLA2は、T細胞性免疫応答に対して促進的に作用することが判明したため免疫療法の新たな標的分子として期待される。さらに簡便に採取可能な血液検体を用いて免疫チェックポイント分子の発現を解析することで悪性度や予後予測を行うことが可能となり、治療方針を決定する上で重要な手助けとなる可能性がある。

Research Products

• [Journal Article] Primary Tumor Score Based on Tumor Depth and Length Predicts Prognosis in Esophageal Squamous Cell Carcinoma (2018)
  • Author(s): ARIGAMI TAKAAKI、UCHIKADO YASUTO、OMOTO ITARU、SASAKI KEN、KITA YOSHIAKI、OWAKI TETSUHIRO、YANAGITA SHIGEHIRO、MORI SHINICHIRO、KURAHARA HIROSHI、OKUMURA HIROSHI、MAEMURA KOSEI、NATSUGOE SHOJI
  • Journal Title: Anticancer Research Volume: 38 Issue: 9 Pages: 5447-5452
  • DOI: 10.21873/anticanres.12876
  • Peer Reviewed
• [Journal Article] The association of human endogenous retrovirus-H long terminal repeat-associating protein 2 (HHLA2) expression with gastric cancer prognosis (2018)
  • Author(s): Shimonosono Masataka、Arigami Takaaki、Yanagita Shigehiro、Matsushita Daisuke、Uchikado Yasuto、Kijima Yuko、Kurahara Hiroshi、Kita Yoshiaki、Mori Shinichiro、Sasaki Ken、Omoto Itaru、Maemura Kosei、Uenosono Yoshikazu、Ishigami Sumiya、Natsugoe Shoji
  • Journal Title: Oncotarget Volume: 9 Issue: 31 Pages: 22069-22078
  • DOI: 10.18632/oncotarget.25179
  • Peer Reviewed / Open Access
• [Journal Article] Clinical significance of primary tumor score determined by tumor depth and size in patients with resectable gastric cancer (2018)
  • Author(s): Haraguchi Naoto、Arigami Takaaki、Uenosono Yoshikazu、Yanagita Shigehiro、Uchikado Yasuto、Mori Shinichiro、Kurahara Hiroshi、Kijima Yuko、Nakajo Akihiro、Maemura Kosei、Ishigami Sumiya、Natsugoe Shoji
  • Journal Title: Oncotarget Volume: 9 Issue: 9 Pages: 8512-8520
  • DOI: 10.18632/oncotarget.23953
  • Peer Reviewed / Open Access
• [Journal Article] Programmed death-ligand 1 is a promising blood marker for predicting tumor progression and prognosis in patients with gastric cancer. (2018)
  • Author(s): Amatatsu M, Arigami T, Uenosono Y, Yanagita S, Uchikado Y, Kijima Y, Kurahara H, Kita Y, Mori S, Sasaki K, Omoto I, Maemura K, Ishigami S, Natsugoe S.
  • Journal Title: Cancer Sci. Volume: 109 Issue: 3 Pages: 814-820
  • DOI: 10.1111/cas.13508
  • Peer Reviewed / Open Access
• [Journal Article] The association of human endogenous retrovirus-H long terminal repeat-associating protein 2 (HHLA2) expression with gastric cancer prognosis (2018)
  • Author(s): Masataka Shimonosono, Takaaki Arigami, Shigehiro Yanagita, Daisuke Matsushita, Yasuto Uchikado, Yuko Kijima, Hiroshi Kurahara, Yoshiaki Kita, Shinichiro Mori, Ken Sasaki, Itaru Omoto, Kosei Maemura, Yoshikazu Uenosono, Sumiya Ishigami, Shoji Natsugoe
  • Journal Title: Oncotarget Volume: 印刷中
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Combined fibrinogen and neutrophil-lymphocyte ratio as a prognostic marker of advanced esophageal squamous cell carcinoma. (2017)
  • Author(s): Kijima T, Ishigami S
  • Journal Title: Cancer Sci Volume: 108 Issue: 2 Pages: 193-199
  • DOI: 10.1111/cas.13127
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Clinical application and outcomes of sentinel node navigation surgery in patients with early gastric cancer (2017)
  • Author(s): Arigami Takaaki、Uenosono Yoshikazu、Yanagita Shigehiro、Okubo Keishi、Kijima Takashi、Matsushita Daisuke、Amatatsu Masahiko、Hagihara Takahiko、Haraguchi Naoto、Mataki Yuko、Ehi Katsuhiko、Ishigami Sumiya、Natsugoe Shoji
  • Journal Title: Oncotarget Volume: 8 Issue: 43 Pages: 75607-75616
  • DOI: 10.18632/oncotarget.17584
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Clinical significance of circulating tumor cells in blood from patients with gastric cancer (2017)
  • Author(s): Arigami Takaaki、Uenosono Yoshikazu、Yanagita Shigehiro、Okubo Keishi、Kijima Takashi、Matsushita Daisuke、Amatatsu Masahiko、Kurahara Hiroshi、Maemura Kosei、Natsugoe Shoji
  • Journal Title: Annals of Gastroenterological Surgery Volume: 1 Issue: 1 Pages: 60-68
  • DOI: 10.1002/ags3.12005
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] 胃癌とリンパ節転移―リンパ行性微小転移の臨床的意義を中心に― (2017)
  • Author(s): 有上貴明, 上之園芳一, 柳田茂寛, 松下大輔, 大久保啓史, 貴島孝, 天辰仁彦, 川越浩輔, 下之薗将貴, 石神純也, 夏越祥次
  • Journal Title: リンパ学 Volume: 40 Pages: 113-116
  • Peer Reviewed
• [Journal Article] Combined fibrinogen concentration and neutrophil-lymphocyte ratio as a prognostic marker of gastric cancer. (2016)
  • Author(s): Arigami T, Uenosono Y, Matsushita D, Yanagita S, Uchikado Y, Kita Y, Mori S, Kijima Y, Okumura H, Maemura K, Ishigami S, Natsugoe S.
  • Journal Title: Oncology Letters Volume: 11 Pages: 1537-1544
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] A Novel Scoring System Based on Fibrinogen and the Neutrophil-Lymphocyte Ratio as a Predictor of Chemotherapy Response and Prognosis in Patients with Advanced Gastric Cancer (2016)
  • Author(s): Takaaki Arigami
  • Journal Title: Oncology Volume: 90 Issue: 4 Pages: 1977-84
  • DOI: 10.1159/000444494
  • Peer Reviewed / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Sentinel node navigation surgery for gastroduodenal neuroendocrine tumors: Two case reports. (2016)
  • Author(s): Arigami T, Uenosono Y, Yanagita S, Okubo K, Kijima T, Matsushita D, Amatatsu M, Hagihara T, Haraguchi N, Mataki Y, Ehi K, Ishigami S, Natsugoe S.
  • Journal Title: Medicine (Baltimore) Volume: 95 Issue: 26 Pages: e4063-e4063
  • DOI: 10.1097/md.0000000000004063
  • Peer Reviewed / Open Access
• [Journal Article] Clinical Impact of Stomach-partitioning Gastrojejunostomy with Braun Enteroenterostomy for Patients with Gastric Outlet Obstruction Caused by Unresectable Gastric Cancer. (2016)
  • Author(s): Arigami T, Uenosono Y, Ishigami S, Yanagita S, Okubo K, Uchikado Y, Kita Y, Mori S, Kurahara H, Maemura K, Natsugoe S.
  • Journal Title: Anticancer Research Volume: 36 Pages: 5431-5436
  • Peer Reviewed
• [Journal Article] Clinical Significance of the Glasgow Prognostic Score in Patients with Gastrointestinal Stromal Tumors. (2016)
  • Author(s): Arigami T, Uenosono Y, Ishigami S, Yanagita S, Okubo K, Uchikado Y, Kita Y, Mori S, Kurahara H, Maemura K, Natsugoe S.
  • Journal Title: Anticancer Research Volume: 36 Pages: 6687-6690
  • Peer Reviewed
• [Presentation] Analysis of PD-L1 Expression and Neutrophil-Lymphocyte Ratio in Peripheral Blood of Gastric Cancer (2018)
  • Author(s): Takaaki Arigami, Masahiko Amatatsu, Shigehiro Yanagita, Daisuke Matsushita, Kosuke Kawagoe, Masataka Shimonosono, Keishi Okubo, Takashi Kijima, Yoshikazu Uenosono, Sumiya Ishigami, Shoji Natsugoe
  • Organizer: 第90回日本胃癌学会総会
• [Presentation] 切除不能・再発胃癌に対する化学療法効果予測因子としてのNeutrophil-Lymphocyte RatioとPlatelet-Lymphocyte Ratioに基づいた血液スコアリングシステムの臨床的意義 (2018)
  • Author(s): 有上貴明, 柳田茂寛, 松下大輔, 川越浩輔, 下之薗将貴, 内門泰斗, 喜多芳昭, 尾本至, 佐々木健, 盛真一郎, 上之園芳一, 夏越祥次
  • Organizer: 第51回制癌剤適応研究会
• [Presentation] 進行胃癌に対するNeutrophil-Lymphocyte RatioとPlatelet-Lymphocyte Ratioの臨床的意義 (2018)
  • Author(s): 有上貴明, 柳田茂寛, 松下大輔, 川越浩輔, 下之薗将貴, 内門泰斗, 尾本至, 佐々木健, 盛真一郎, 喜多芳昭, 田辺寛, 上之園芳一, 石神純也, 夏越祥次
  • Organizer: 第39回癌免疫外科研究会
• [Presentation] 胃癌における免疫チェックポイント分子B7-H3およびB7-H4発現の臨床的意義と個別化治療への応用 (2017)
  • Author(s): 有上貴明, 上之園芳一, 大久保啓史, 貴島孝, 天辰仁彦, 川越浩輔, 柳田茂寛, 内門泰斗, 喜多芳昭, 尾本至, 佐々木健, 盛真一郎, 馬場研二, 石神純也, 夏越祥次
  • Organizer: 第50回制癌剤適応研究会
• [Presentation] 切除不能進行・再発胃癌における炎症と宿主免疫機能の関係：C-reactive proteinとNeutrophil-Lymphocyte Ratioの観点から (2017)
  • Author(s): 有上貴明, 上之園芳一, 大久保啓史, 貴島孝, 天辰仁彦, 川越浩輔, 内門泰斗, 盛真一郎, 喜多芳昭, 柳田茂寛, 石神純也, 夏越祥次
  • Organizer: 第38回癌免疫外科研究会
• [Presentation] 胃癌における血小板数と血清Fibrinogenの臨床的意義：腫瘍進行度や予後の予測に有用な凝固系スコア―の検討 (2017)
  • Author(s): 有上貴明, 上之園芳一, 大久保啓史, 貴島孝, 天辰仁彦, 川越浩輔, 石神純也,柳田茂寛, 夏越祥次
  • Organizer: 第72回日本消化器外科学会総会
• [Presentation] 胃癌に対する次世代の免疫療法ターゲットとしてのB7-H3およびB7-H4免疫チェックポイント分子―Liquid biopsyとしての血液検体を用いた個別化治療への応用― (2017)
  • Author(s): 有上貴明, 上之園芳一, 柳田茂寛, 大久保啓史, 貴島孝, 天辰仁彦, 川越浩輔, 松下大輔, 内門泰斗, 喜多芳昭, 尾本至, 佐々木健, 盛真一郎, 石神純也, 夏越祥次
  • Organizer: 第79回日本臨床外科学会総会
• [Presentation] Gastrointestinal stromal tumor (GIST) に対する再発予測マーカーとしてのGlasgow Prognostic Scoreの臨床的意義―Fletcher分類との比較検討― (2016)
  • Author(s): 有上貴明, 上之園芳一, 大久保啓史, 貴島孝, 天辰仁彦, 内門泰斗, 喜多芳昭, 盛真一郎, 柳田茂寛, 石神純也, 夏越祥次
  • Organizer: 第116回日本外科学会定期学術集会
  • Place of Presentation: 大阪国際会議場（大阪府大阪市）
• [Presentation] B7-H3 Ligand Expression by Primary Breast Cancer and Associated with Regional Nodal Metastasis (2016)
  • Author(s): Takaaki Arigami, Norihiko Narita, Ryuichi Mizuno, Linhda Nguyen, Xing Ye, Shoji Natsugoe, Dave S.B. Hoon
  • Organizer: 第37回癌免疫外科研究会
  • Place of Presentation: 川越プリンスホテル（埼玉県川越市）
• [Presentation] 胃癌に対するNeutrophil-Lymphocyte RatioとPlatelet-Lymphocyte Ratioの臨床的意義―炎症関連血液マーカーとしての有用性― (2016)
  • Author(s): 有上貴明, 上之園芳一, 大久保啓史, 貴島孝, 天辰仁彦, 柳田茂寛, 内門泰斗, 喜多芳昭, 尾本至, 佐々木健, 盛真一郎, 馬場研二, 石神純也, 夏越祥次
  • Organizer: 第27回日本消化器癌発生学会総会
  • Place of Presentation: 城山観光ホテル（鹿児島県鹿児島市）
• [Presentation] 切除不能胃癌に対するNeutrophil-Lymphocyte RatioとPlatelet-Lymphocyte Ratioの意義 (2016)
  • Author(s): 有上貴明, 上之園芳一, 大久保啓史, 貴島孝, 天辰仁彦, 内門泰斗, 盛真一郎, 喜多芳昭,柳田茂寛, 石神純也, 夏越祥次
  • Organizer: 第54回日本癌治療学会学術集会
  • Place of Presentation: パシフィコ横浜（神奈川県横浜市）
• [Book] 日本臨床 特集 胃癌―診断・治療の最新知見― 総論 第15版胃癌取扱い規約のポイント (2018)
  • Author(s): 有上貴明, 柳田茂寛, 夏越祥次
  • Total Pages: 5
  • Publisher: 日本臨床社