Elucidation of immune system and search for innovative biomarkers in peritoneal dissemination of gastric cancer

• Project/Area Number: 19K18095
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 55020:Digestive surgery-related
• Research Institution: Kumamoto University
• Principal Investigator: KIYOZUMI Yuuki 熊本大学, 病院, 非常勤診療医師 (30827324)
• Project Period (FY): 2019-04-01 – 2021-03-31
• Project Status: Completed (Fiscal Year 2020)
• Budget Amount: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000); Fiscal Year 2020: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000); Fiscal Year 2019: ¥2,340,000 (Direct Cost: ¥1,800,000、Indirect Cost: ¥540,000)
• Keywords: 胃癌 / 免疫寛容 / 免疫チェックポイント阻害薬 / 不均一性 / 腹膜播種 / PD-1 / PD-L1 / IDO1 / バイオマーカー / リキッドバイオプシー / 免疫療法

Outline of Research at the Start

本研究では、非常に予後不良の病態である胃癌腹膜播種に対して、細胞障害性T細胞のアポトーシスやTregを誘導して免疫寛容を促すIDO1に着目し、治療効果予測バイオマーカーの確立を行うために、胃癌における免疫学的因子の免疫染色、血清サンプルと腫瘍組織における免疫学的因子発現の比較、Microarray解析、モデルマウスによる実験等を行う。更に胃癌腹膜播種症例におけるがん免疫細胞発現パターンとそのメカニズムを明らかにすることで、バイオマーカーの実用性の裏づけを行い、リキッドバイオプシーで測定する手法を確立する。

Outline of Final Research Achievements

PD-L1 expression as a predictive biomarker for PD-1 inhibitor efficacy in gastric cancer (GC) remains controversial. Firstly, PD-L1 expressions in biopsy and paired resected samples by IHC staining were compared according to the number of biopsies. Single biopsy showed a lower accordance rate compared with multiple biopsies. Therefore, Multiple biopsies are recommended for accurate diagnosis of PD-L1 expression in GC. Secondly, we aimed to elucidate the effects of trastuzumab (Tmab) on PD-L1 expression in GC. PD-L1 expression was upregulated by Tmab in HER2-amplified GC cell lines co-cultured with peripheral blood mononuclear cells. PD-L1 upregulation by Tmab was also observed in the GC cells co-cultured with NK cells in time-dependent manner, but not with monocytes. Tmab can upregulate PD-L1 expression on GC cells through interaction with NK cells. These results suggest clinical implications in the assessment of predictive significance of PD-L1 expression for PD-1 inhibitors.

Academic Significance and Societal Importance of the Research Achievements

胃癌に対する免疫チェックポイント阻害薬の効果を予測するうえで重要と考えられる、免疫関連因子の発現の空間的不均一性、経時的不均一性を評価するために、本研究を行った。その結果、複数回の生検を行わないと免疫関連因子の発現を正確に評価できないことや、化学療法が発現に影響与えることを証明できたため、今後の臨床における治療予測因子として重要な役割を果たすと考えられる。

Research Products

• [Journal Article] Trastuzumab upregulates programmed death ligand-1 expression through interaction with NK cells in gastric cancer (2020)
  • Author(s): Yamashita Kohei、Iwatsuki Masaaki、Yasuda-Yoshihara Noriko、Morinaga Takeshi、Nakao Yosuke、Harada Kazuto、Eto Kojiro、Kurashige Junji、Hiyoshi Yukiharu、Ishimoto Takatsugu、Nagai Yohei、Iwagami Shiro、Baba Yoshifumi、Miyamoto Yuji、Yoshida Naoya、Ajani Jaffer A.、Baba Hideo
  • Journal Title: British Journal of Cancer Volume: 124 Issue: 3 Pages: 595-603
  • DOI: 10.1038/s41416-020-01138-3
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Programmed death ligand-1 expression in gastrointestinal cancer: its clinical significance and challenging issues. (2020)
  • Author(s): Yamashita K, Iwatsuki M, Ajani JA, Baba H
  • Journal Title: Ann Gastroenterol Surg
  • Peer Reviewed
• [Journal Article] Clinical utility and future perspectives of liquid biopsy in gastrointestinal cancer (2020)
  • Author(s): Yamashita K, Harada K, Ajani JA
  • Journal Title: Future Oncol
  • Peer Reviewed
• [Journal Article] Prognostic impacts of the combined positive score and the tumor proportion score for programmed death ligand-1 expression by double immunohistochemical staining in patients with advanced gastric cancer. (2020)
  • Author(s): Yamashita K, Iwatsuki M, Harada K, Eto K, Hiyoshi Y, Ishimoto T, Nagai Y, Iwagami S, Miyamoto Y, Yoshida N, Komohara Y, Ajani JA, Baba H
  • Journal Title: Gastric Cancer. Volume: 23(1) Issue: 1 Pages: 95-104
  • DOI: 10.1007/s10120-019-00999-9
  • Peer Reviewed
• [Journal Article] Indoleamine 2, 3‐dioxygenase 1 promoter hypomethylation is associated with poor prognosis in patients with esophageal cancer (2019)
  • Author(s): Kiyozumi Yuki、Baba Yoshifumi、Okadome Kazuo、Yagi Taisuke、Ogata Yoko、Eto Kojiro、Hiyoshi Yukiharu、Ishimoto Takatsugu、Iwatsuki Masaaki、Iwagami Shiro、Miyamoto Yuji、Yoshida Naoya、Watanabe Masayuki、Baba Hideo
  • Journal Title: Cancer Science Volume: 110(6) Issue: 6 Pages: 1863-1871
  • DOI: 10.1111/cas.14028
  • Peer Reviewed / Open Access
• [Journal Article] Can PD-L1 expression evaluated by biopsy sample accurately reflect its expression in the whole tumour in gastric cancer? (2019)
  • Author(s): Yamashita K, Iwatsuki M, Harada K, Koga Y, Kiyozumi Y, Eto K, Hiyoshi Y, Ishimoto T, Iwagami S, Baba Y, Miyamoto Y, Yoshida N, Komohara Y, Ajani JA, Baba H
  • Journal Title: Br J Cancer. Volume: 121(3) Pages: 278-280
  • Peer Reviewed
• [Presentation] Chemotherapy induces upregulation of programmed death ligand-1 expression in gastric cancer. (2019)
  • Author(s): Kohei Yamashita, Masaaki Iwatsuki, Shiro Iwagami, Kojiro Eto, Yuki Koga, Yuki Kiyozumi, Yoshifumi Baba, Naoya Yoshida, Hideo Baba.
  • Organizer: American Association for Cancer Research
  • Int'l Joint Research
• [Presentation] 5-FU induces upregulation of PD-L1 expression in gastric cancer. (2019)
  • Author(s): Kohei Yamashita, Masaaki Iwatsuki, Kojiro Eto, Yukiharu Hiyoshi, Takatsugu Ishimoto, Yohei Nagai, Shiro Iwagami, Yuji Miyamoto, Naoya Yoshida and Hideo Baba.
  • Organizer: 第78回日本癌学会学術総会
• [Presentation] Can PD-L1 expression by biopsy specimen accurately reflect its expression of the entire tumor in gastric cancer? (2019)
  • Author(s): Kohei Yamashita, Masaaki Iwatsuki, Yuki Koga, Yuki Kiyozumi, Kojiro Eto, Yukiharu Hiyoshi, Shiro Iwagami, Yoshifumi Baba, Yuji Miyamoto, Naoya Yoshida and Hideo Baba.
  • Organizer: 第77回日本癌学会学術総会