To predict and improve the response to neoadjuvant chemotherapy in gastric cancer, targeting for immunological factor

Research Project

Project/Area Number	18K16308
Research Category	Grant-in-Aid for Early-Career Scientists
Allocation Type	Multi-year Fund
Review Section	Basic Section 55020:Digestive surgery-related
Research Institution	Osaka University
Principal Investigator	Urakawa Shinya 大阪大学, 医学系研究科, 特任助教(常勤) (40768975)
Project Period (FY)	2018-04-01 – 2020-03-31
Project Status	Completed (Fiscal Year 2019)
Budget Amount *help	¥4,030,000 (Direct Cost: ¥3,100,000、Indirect Cost: ¥930,000) Fiscal Year 2019: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000) Fiscal Year 2018: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
Keywords	術前化学療法 / Tim-3 / 胃がん / 食道がん / PD-1 / 胃癌 / Tim3 / オフターゲット効果 / 腫瘍免疫
Outline of Final Research Achievements	Immune cells extracted from pre- and post-neoadjuvant chemotherapy fresh tumor tissues in gastric cancer were analyzed by flow cytometry. The unique immune cells in CD8+ cells, which expressed only Tim-3, not PD-1, were found (Tim-3+ PD-1- in CD8+ cells). These immune cells showed higher expression of granzyme B and perforin than other cells. On the other hands, Tim-3+ PD-1- in CD8+ cells were not observed in esophageal tumor tissues after neoadjuvant chemotherapy. % PD-1+ Tim-3+ in CD8+ cells was conversely associated with the response to neoadjuvant chemotherapy. These cells showed low expression of granzyme B, perforin and IFN-g. Our findings indicate that Tim-3+ PD-1- in CD8+ cells, which might have anti-tumor immunity, is specific to gastric tumor tissues or anti-cancer agents used for gastric cancer.
Academic Significance and Societal Importance of the Research Achievements	本研究の結果は、特定条件下では、化学療法によって抗腫瘍効果をより有する細胞群が出現する可能性を示した。また、食道がんのようにTim-3分子を発現した細胞は、様々ながん種で予後不良の因子と報告されてきた。本研究の結果はこれらと異なるものであり、Tim-3分子の新しい知見につながる。現在、手術前もしくは手術後・再発後の治療選択肢として、免疫療法の導入が検討されており、予後改善に寄与する結果も出始めている。加えて、本研究は化学療法と免疫療法との併用が予後改善につながる可能性を示唆する。