2022 Fiscal Year Final Research Report

Development of intraperitoneal immunotherapy for peritoneal metastasis

Research Project

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Project/Area Number	20K08989
Research Category	Grant-in-Aid for Scientific Research (C)
Allocation Type	Multi-year Fund
Section	一般
Review Section	Basic Section 55010:General surgery and pediatric surgery-related
Research Institution	Jichi Medical University
Principal Investigator	Yamaguchi Hironori 自治医科大学, 医学部, 教授 (20376445)
Co-Investigator(Kenkyū-buntansha)	北山丈二自治医科大学, 医学部, 教授 (20251308) 佐田友藍自治医科大学, 医学部, 助教 (40528585) 伊藤大知東京大学, 大学院医学系研究科(医学部), 教授 (50447421) 相澤健一自治医科大学, 医学部, 准教授 (70436484) 宮戸秀世自治医科大学, 医学部, 講師 (90813163)
Project Period (FY)	2020-04-01 – 2023-03-31
Keywords	腹膜播種 / 免疫チェックポイント阻害 / 抗PD-１抗体 / 腫瘍浸潤リンパ球 / 骨髄由来抑制性細胞 / フィブロネクチン
Outline of Final Research Achievements	Intraperitoneal (IP) inoculation of a highly metastatic subclone of murine gastric cancer, YTN16P2, (1x106) resulted in multiple mesenteric metastases after 3 weeks. Intravenous (IV) or IP administration of anti-PD-1mAb reduced the number of metastases to the mesentery by 40~50% compared with isotype controls. However, no differences were observed depending on the route of administration. Although splenocyte phenotypes were not altered, the densities of CD8(+) T cells in peritoneal tumors were significantly increased, while those of Gr-1(+) myeloid derived suppressor cells (MDSC) were significantly reduced in mice treated with anti-PD-1 mAb.PD-1 blockade therapy remodels the cellular immune composition of peritoneal tumors which can partially suppress the peritoneal metastasis regardless of the route of administration. Anti-PD-1 mAb may enhance the effects of chemotherapeutic agents, leading to the better outcome of patients with gastric cancer with peritoneal involvement.
Free Research Field	臨床腫瘍学
Academic Significance and Societal Importance of the Research Achievements	胃癌腹膜播種に対する免疫チェックポイント阻害抗体の治療効果に関する基礎データは少ない。本研究で新たに作成したマウスモデルは様々な免疫療法の効果と作用機序を解明する上で大変有用である。今回、抗PD-1抗体は全身または腹腔内投与で腹膜播種を部分的に抑制することが確認された。その治療効果は予想と異なり投与経路によって顕著な差は認めなかったが、この抗体には腹膜播種巣内へのT細胞の浸潤を促進し、免疫抑制性のMDSCの浸潤を抑制する作用があり、これが播種抑制効果と関連する可能性があるという重要な新知見を得ることができた。