Anti-tumor activity in LPS tolerance and development of new technology on clinical application of tolerance

• Project/Area Number: 17K10682
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Digestive surgery
• Research Institution: Saitama Medical University
• Principal Investigator: MORIYA TOMOYUKI 埼玉医科大学, 医学部, 客員准教授 (10531303)
• Co-Investigator(Kenkyū-buntansha): 山本 順司 東京大学, 医学部附属病院, 登録研究員 (40342654) ; 木下 学 防衛医科大学校(医学教育部医学科進学課程及び専門課程、動物実験施設、共同利用研究施設、病院並びに防衛, 免疫・微生物学, 准教授 (70531391) ; 守本 祐司 防衛医科大学校(医学教育部医学科進学課程及び専門課程、動物実験施設、共同利用研究施設、病院並びに防衛, 生理学, 教授 (10449069) ; 青笹 季文 防衛医科大学校(医学教育部医学科進学課程及び専門課程、動物実験施設、共同利用研究施設、病院並びに防衛, 外科学, 准教授 (40649034) ; 野呂 拓史 獨協医科大学, 医学部, 講師 (10385346)
• Project Period (FY): 2017-04-01 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000); Fiscal Year 2019: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2018: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2017: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
• Keywords: 抗腫瘍活性 / 免疫学 / 周術期管理 / LPSトレランス / 大腸がん / 転移性肝がん / 免疫療法 / 腫瘍免疫 / 抗腫瘍効果 / 肝臓外科学

Outline of Final Research Achievements

To investigate the effect of LPS preconditioning on antitumor activity against Colon26 tumor cells in mice.　 Mice were induced LPS preconditioning by intraperitoneal injections of 5 μg/kg LPS for three consecutive days, and they received intraportal inoculation of Colon26 cells. LPS preconditioning prevented liver metastasis and prolonged mouse survivals after intraportal inoculation of Colon26 cells. LPS preconditioning increased perforin and granzyme B expression in the liver natural killer (NK) and NKT cells and augmented their antitumor cytotoxicities against Colon26 cells. LPS preconditioning potently augmented antitumor cytotoxicity of liver NK cells and NKT cells, thereby improving mouse survival after intraportal inoculation of Colon26 tumor cells.

Academic Significance and Societal Importance of the Research Achievements

極微量のlipopolysaccharide (LPS）であらかじめ刺激することで生じるLPSトレランスの抗腫瘍活性に関しては、これまで報告がなく、その効果は不明なままであった。本研究で、LPSトレランスに抗腫瘍活性があり、その機序の一部が解明されたことは外科臨床・免疫分野において極めて有用な知見と考えられる。本研究の結果、LPSトレランスが消化器外科領域で新しいがん治療の一つの選択肢となる可能性が示され、治療成績のさらなる向上、予後の改善に希望がもたらされた。社会的意義のある研究成果と考えられた。

Research Products

• [Journal Article] Lipopolysaccharide preconditioning reduces liver metastasis of Colon26 cells by enhancing antitumor activity of natural killer cells and natural killer T cells in murine liver (2020)
  • Author(s): Nishikawa Makoto、Kinoshita Manabu、Morimoto Yuji、Ishikiriyama Takuya、Nakashima Masahiro、Nakashima Hiroyuki、Ono Takeshi、Seki Shuhji、Moriya Tomoyuki、Yamamoto Junji、Kishi Yoji
  • Journal Title: Journal of Gastroenterology and Hepatology Volume: Online Issue: 7 Pages: 1889-1898
  • DOI: 10.1111/jgh.15375
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] 侵襲時の腸管免疫能とホエイタンパク投与 (2019)
  • Author(s): 守屋 智之
  • Journal Title: 外科と代謝・栄養 Volume: 53 Pages: 275-280
  • NAID: 130007784965
  • Peer Reviewed
• [Journal Article] Immune mechanisms underlying susceptibility to endotoxin shock in aged hosts: implication in age-augmented generalized Shwartzman reaction (2019)
  • Author(s): Kinoshita M, Nakashima M, Nakashima H, Seki S
  • Journal Title: Int J Mol Sci Volume: 20 Issue: 13 Pages: 3260-3260
  • DOI: 10.3390/ijms20133260
  • Peer Reviewed / Open Access
• [Journal Article] The reduced bactericidal activity of neutrophils as an incisive indicator of water-immersion restraint stress and impaired exercise performance in mice (2019)
  • Author(s): Kinoshita M, Nakashima, H, Nakashima M, Koga M, Toda H, Koiwi K, Morimoto Y, Miyazaki H, Saitoh D, Suzuki H, Seki S
  • Journal Title: Sci Rep Volume: 9 Issue: 1 Pages: 4662-4662
  • DOI: 10.1038/s41598-019-41077-5
  • Peer Reviewed / Open Access
• [Journal Article] Pioglitazone improves phagocytic activity of liver recruited macrophages in elderly mice possibly by promoting glucose catabolism (2019)
  • Author(s): Nakashima M, Kinoshita M, Nakashima H, Kotani A, Ishikiriyama T, Kato S, Hiroi S, Seki S
  • Journal Title: Innate Immun Volume: 25 Issue: 6 Pages: 356-368
  • DOI: 10.1177/1753425919849620
  • Peer Reviewed / Open Access
• [Journal Article] In situ transplantation of adipose tissue-derived stem cells organized on porous polymer nanosheets for murine skin defects (2018)
  • Author(s): Nishiwaki Keisuke、Aoki Shimpo、Kinoshita Manabu、Kiyosawa Tomoharu、Suematsu Yoshitaka、Takeoka Shinji、Fujie Toshinori
  • Journal Title: Journal of Biomedical Materials Research Part B: Applied Biomaterials Volume: 印刷中 Issue: 5 Pages: 3061-3168
  • DOI: 10.1002/jbm.b.34228
  • Peer Reviewed
• [Journal Article] Effects of semielemental diet containing whey peptides on Peyer's patch lymphocyte number, immunoglobulin A levels, and intestinal morphology in mice. (2018)
  • Author(s): Moriya T, Fukatsu K, Noguchi M, Nishikawa M, Miyazaki H, Saitoh D, Ueno H, Yamamoto J.
  • Journal Title: J Surg Res. Volume: 222 Pages: 153-159
  • DOI: 10.1016/j.jss.2017.10.015
  • Peer Reviewed
• [Presentation] Endotoxin tolerance reinforces anti-tumor activity of hepatic immune cells in mice (2018)
  • Author(s): Moriya T
  • Organizer: 2019 ASPEN Nutrition Science & Practice Conference
  • Int'l Joint Research
• [Presentation] Effects of semi-elemental diet containing whey peptides on peyer patch lymphocyte number, immunoglobulin A levels and intestinal morphology in mice (2017)
  • Author(s): Tomoyuki Moriya
  • Organizer: ASPEN 2018
  • Int'l Joint Research