Biological Features of Inflammatory Bowel Disease-Associated Colorectal Cancer and the Association of Innate Lymphoid Cells

Research Project

Project/Area Number	17K10631
Research Category	Grant-in-Aid for Scientific Research (C)
Allocation Type	Multi-year Fund
Section	一般
Research Field	Digestive surgery
Research Institution	Osaka University
Principal Investigator	Mizushima Tsunekazu 大阪大学, 医学系研究科, 寄附講座教授 (00527707)
Co-Investigator(Kenkyū-buntansha)	松田宙大阪大学, 医学系研究科, 准教授 (00379207)
Project Period (FY)	2017-04-01 – 2020-03-31
Project Status	Completed (Fiscal Year 2019)
Budget Amount *help	¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000) Fiscal Year 2019: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000) Fiscal Year 2018: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000) Fiscal Year 2017: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
Keywords	自然リンパ球 / 大腸癌 / 炎症性腸疾患 / 腸炎関連大腸癌 / 炎症性腸疾患関連癌 / 小腸大腸肛門外科学
Outline of Final Research Achievements	In this study, we identified distinct subsets of human innate lymphoid cells (ILCs) in normal colonic mucosa, colorectal cancer (CRC), and colonic mucosa of ulcerative colitis (UC) by isolating lymphocytes from surgically resected specimens. NKp44+ ILC3s, which were abundant in normal colonic mucosa compared to other ILC subsets, were associated with formation of tertiary lymphoid structures (TLSs) and induction of subsequent anti-tumor immunity in CRC. Although we could not conduct enough analysis due to the rarity of disease, ILC3s derived from colonic mucosa of patients with UC expressed significantly high level of IL-22. This result suggests that IL22-producing-ILC3s might contribute to the tumor growth of UC-associated colorectal cancers, as demonstrated in murine studies previously.
Academic Significance and Societal Importance of the Research Achievements	ヒト通常型大腸癌や炎症性腸疾患（IBD）関連癌の腫瘍組織において、どのような免疫環境が作り出されているのか、その解析は発展途上である。ILCは腸管免疫で重要な役割を担うリンパ球であり、IBDの病因・病態への関与が示されつつあるが、大腸癌におけるILCについて解析した報告はなかった。本研究で、ヒト大腸粘膜、通常型大腸癌組織、UC粘膜に存在するILC分画を明らかとし、通常型大腸癌においてはTLS形成ならびに抗腫瘍免疫誘導への関与が示され、新規治療開発につながる結果を得た。UC関連癌に関しては、通常型大腸癌と全く異なる機序でILCが腫瘍免疫に関与している可能性が考えられ、今後更なる研究が期待される。