Analysis of immunosuppression by ER stress in cancer microenvironments

2023 Fiscal Year Final Research Report

• Project/Area Number: 21H02785
• 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: Kyoto University
• Principal Investigator: Yaguchi Tomonori 京都大学, 医学研究科, 特定講師 (40424163)
• Project Period (FY): 2021-04-01 – 2024-03-31
• Keywords: 腫瘍免疫 / ERストレス

Outline of Final Research Achievements

Immunosuppression is the main cause of resistance to immune checkpoint inhibitors. In this study, we examined the role of endoplasmic reticulum (ER) stress in T cells in this immunosuppression. Inhibitors of stearoyl-CoA desaturase 1 (SCD-1), an enzyme involved in fatty acid metabolism, reduced ER stress in T cells and enhanced the therapeutic effect of anti-PD-1 antibody through enhancing T cells function. (Kato et al. J Immunother Cancer. 2022). Furthermore, we found that a metabolite, which are reported to decrease with aging, binds to a protein involved in ER stress and enhances its function. These findings suggest that ER stress increase with aging, leading to the dysfunction of T cells.

Free Research Field

腫瘍免疫

Academic Significance and Societal Importance of the Research Achievements

ERストレスと抗腫瘍免疫応答の関連に関して、SCD-1の関与、老化の関与が明らかとなり、ERストレスの制御で、免疫チェックポイント阻害薬(ICI)の効果を増強できることが分かった。本研究の成果は、基礎医学的なヒトがん免疫病態の解明に貢献できるだけでなく、ICIの課題である症例選択のためのバイオマーカー開発や治療改良法の開発など、臨床医学的にも多大な貢献ができ、波及効果が高い研究と考えられる。