2022 Fiscal Year Final Research Report

Elucidation and control of immunosuppressive mechanisms by oncogenes and abnormal lipid metabolism in the tumor microenvironment

Research Project

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Project/Area Number	20H03534
Research Category	Grant-in-Aid for Scientific Research (B)
Allocation Type	Single-year Grants
Section	一般
Review Section	Basic Section 50020:Tumor diagnostics and therapeutics-related
Research Institution	International University of Health and Welfare (2021-2022) Keio University (2020)
Principal Investigator	Kawakami Yutaka 国際医療福祉大学, 医学部, 教授 (50161287)
Co-Investigator(Kenkyū-buntansha)	久保亜紀子慶應義塾大学, 医学部(信濃町), 助教 (50455573) 潮見隆之国際医療福祉大学, 医学部, 教授 (80348797)
Project Period (FY)	2020-04-01 – 2023-03-31
Keywords	がん微小環境 / がん遺伝子 / 脂質代謝 / 免疫抑制 / 免疫チェックポイント阻害薬
Outline of Final Research Achievements	In this study, we found that SCD1, a fatty acid metabolizing enzyme, is expressed in cancer cells and immune cells including T cells, and suppresses anti-tumor immune responses. In cancer cells, SCD1 reduced chemokine production partly through β-catenin signaling, resulting in suppression of tumor infiltration of dendritic cells and subsequent T cell induction. SCD1 also impaired T cell function directly via increasing ER stress. Administration of SCD1 inhibitors to mouse tumor models enhanced the induction and tumor infiltration of dendritic cells and anti-tumor CD8+ T cells, and its combined use with anti-PD-1 antibody enhanced the therapeutic effect. In lung cancer patients treated with anti-PD-1 antibody, serum SCD1-related fatty acids at baseline were correlated with response rate and prognosis. Therefore, SCD1 is one of the immunoresistance mechanisms, and a potential diagnostic and therapeutic target for cancer immunotherapy.
Free Research Field	腫瘍免疫学
Academic Significance and Societal Importance of the Research Achievements	二人に一人ががんになる時代となり、がん治療のさらなる改善が期待されている。がん免疫療法、特に免疫チェックポイント阻害薬は、すでに標準的がん治療となったが、治療効果はまだ限定的であり、免疫抵抗性機序の解明とその改善によるがん免疫療法の改良が世界中で試みられている。本研究では、脂肪酸代謝酵素SCD1が免疫チェックポイント阻害薬の抵抗性機序になること、またその細胞・分子機構をマウス腫瘍モデルとヒトがん症例で明らかにした。本研究成果は、腫瘍免疫学の進歩だけでなく、免疫チェックポイント阻害薬とSCD1阻害薬を併用する複合がん免疫療法開発につながると期待される。