Enhancement of antitumor activity by epigenetic regulation of tumor-specific T cells

2022 Fiscal Year Final Research Report

• Project/Area Number: 20K07680
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 50020:Tumor diagnostics and therapeutics-related
• Research Institution: Ehime Prefectural University of Health Science
• Principal Investigator: Takeshi Yamada 愛媛県立医療技術大学, 保健科学部, 教授 (40333554)
• Project Period (FY): 2020-04-01 – 2023-03-31
• Keywords: 抗腫瘍免疫 / CD8 T細胞 / エピジェネティック

Outline of Final Research Achievements

Our culture experiment of mouse CD8 T cells using GSK-J4, a drug that inhibits histone H3K27 demethylase, revealed that T cell exhaustion was suppressed and memory differentiation, which plays a role in long-term immunity, was promoted. Furthermore, we clarified that BPTES, an inhibitor of the glutamine metabolic pathway that activates this demethylase, has the same effect. Based on these results, we used tumor-bearing mice to investigate whether the antitumor effect of CD8 T cells adoptive transferred into the mice was actually increased by the use of these inhibitors. We confirmed that tumor growth was suppressed more efficiently in the group of CD8 T cells cultured with GSK-J4 or BPTES than in the group of control CD8 T cells cultured without any inhibitors.

Free Research Field

腫瘍免疫学

Academic Significance and Societal Importance of the Research Achievements

長期免疫の獲得に重要な記憶（メモリー）T細胞分化の誘導は、難治性がん克服のための重要な研究課題と考えられる。実用的なワクチンや免疫療法の開発を行う上で、T細胞分化メカニズムの理解は不可欠であるが、その分化を制御するエピジェネティック調節機構については、まだ明らかとなっていない。そこで本研究は、CD8 T細胞におけるヒストン脱メチル化酵素の役割に焦点を当てた解析を行い、エピジェネティック変化によるメモリーCD8 T細胞分化の制御メカニズムの一部を明らかにした。これらの成果は、エピジェネティック調節をすることで人為的にT細胞分化制御を行い、腫瘍に対する長期免疫を誘導できることが期待できる。