Elucidating the differentiation mechanisms of PD-1 positive regulatory T cells in the tumor microenvironment by single-cell analysis.

• Project/Area Number: 21K07112
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 50010:Tumor biology-related
• Research Institution: National Cancer Center Japan
• Principal Investigator: Irie Takuma 国立研究開発法人国立がん研究センター, 先端医療開発センター, 研究員 (50625944)
• Project Period (FY): 2021-04-01 – 2024-03-31
• Project Status: Completed (Fiscal Year 2023)
• Budget Amount: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000); Fiscal Year 2023: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000); Fiscal Year 2022: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000); Fiscal Year 2021: ¥2,340,000 (Direct Cost: ¥1,800,000、Indirect Cost: ¥540,000)
• Keywords: 制御性T細胞 / 腫瘍浸潤T細胞 / シングルセル解析 / scRNA-seq / scATAC-seq / シングルセルRNA-seq / シングルセルATAC-seq / 腫瘍浸潤リンパ球 / 腫瘍微少環境 / 腫瘍免疫学 / PD-1 / ATAC-seq

Outline of Research at the Start

腫瘍局所のTregのシングルセルRNA-seqとシングルセルATAC-seq解析によって、腫瘍環境下におけるTregの機能分化、特にPD-1陽性制御性T細胞への分化過程を明らかにする。情報学的解析によりTreg中のPD-1の発現制御や分化に関わる転写因子、エンハンサー領域を抽出し、推定された転写因子、エンハンサー領域をin vitro, in vivoの実験的に検証する。以上を通じて腫瘍環境中のTregの分化の制御メカニズムを明らかにし、将来的にTregをターゲットとした薬剤開発の可能性や免疫チェックポイント阻害剤の効果予測バイオマーカーの同定を目指す。

Outline of Final Research Achievements

Through analysis of clinical samples treated with immune checkpoint inhibitors, our laboratory has found PD-1-positive regulatory T cells to be an important biomarker to predict efficacy. However, there are few studies on tumor-infiltrating PD-1-positive regulatory T cells, the mechanisms of differentiation leading to their characteristic phenotype and their differences from other regulatory T cells. In this study, through single-cell analysis of tumor-infiltrating regulatory T cells, we show that the transcription factor BATF functions as the core of a transcription factor network that differentiates into PD-1-positive regulatory T cells within tumors.

Academic Significance and Societal Importance of the Research Achievements

本研究では、転写因子BATFが、がん組織内の制御性T細胞のクロマチンのリモデリングに重要であり、　制御性T細胞の活性化プログラムの中核を担っていることを発見した。本研究による成果は、がん組織内の制御性T細胞を標的とする免疫治療開発や制御性T細胞が発症に関わる自己免疫性疾患の理解、様々な医学研究に応用されることが期待される。

Research Products

• [Journal Article] Bronchoalveolar lavage fluid reveals factors contributing to the efficacy of PD-1 blockade in lung cancer (2022)
  • Author(s): Masuhiro Kentaro、Tamiya Motohiro、Fujimoto Kosuke
  • Journal Title: JCI Insight Volume: 1 Issue: 9 Pages: 1-1
  • DOI: 10.1172/jci.insight.157915
  • Peer Reviewed / Open Access
• [Journal Article] PD-1 blockade therapy promotes infiltration of tumor-attacking exhausted T cell clonotypes (2022)
  • Author(s): Nagasaki Joji、Inozume Takashi、Yosuke Togashi et al.
  • Journal Title: Cell Reports Volume: 38 Issue: 5 Pages: 110331-110331
  • DOI: 10.1016/j.celrep.2022.110331
  • NAID: 120007192058
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Regulatory T‐cell development in the tumor microenvironment (2022)
  • Author(s): Itahashi Kota、Irie Takuma、Nishikawa Hiroyoshi
  • Journal Title: European Journal of Immunology Volume: 52 Issue: 8 Pages: 1216-1227
  • DOI: 10.1002/eji.202149358
  • Peer Reviewed / Open Access
• [Journal Article] BATF epigenetically and transcriptionally controls the activation program of regulatory T cells in human tumors (2022)
  • Author(s): Itahashi Kota、Irie Takuma、Yuda Junichiro、Kumagai Shogo、Tanegashima Tokiyoshi、Lin Yi-Tzu、Watanabe Sho、Goto Yasushi、Suzuki Jun、Aokage Keiju、Tsuboi Masahiro、Minami Yosuke、Ishii Genichiro、Ohe Yuichiro、Ise Wataru、Kurosaki Tomohiro、Suzuki Yutaka、Koyama Shohei、Nishikawa Hiroyoshi
  • Journal Title: Science Immunology Volume: 7 Issue: 76 Pages: 1-20
  • DOI: 10.1126/sciimmunol.abk0957
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Lactic acid promotes PD-1 expression in regulatory T cells in highly glycolytic tumor microenvironments (2022)
  • Author(s): Kumagai S, Koyama S, Itahashi K, Tanegashima T, Lin YT, Togashi Y, Kamada T, Irie T, Okumura G, Kono H, Ito D, Fujii R, Watanabe S, Sai A, Aokage K, Suzuki J, Ishii G, Kuwata T, Sakamoto N, Kawazu M, Ueno T, Mori T, Yamazaki N, Tsuboi M, Yatabe Y, Kinoshita T, Doi T, Shitara K, Mano H, Nishikawa H
  • Journal Title: Cancer Cell Volume: 40 Issue: 2 Pages: 201-218
  • DOI: 10.1016/j.ccell.2022.01.001
  • Peer Reviewed / Open Access
• [Journal Article] Depletion of central memory CD8+ T cells might impede the antitumor therapeutic effect of Mogamulizumab (2021)
  • Author(s): Maeda Yuka、Wada Hisashi、Sugiyama Daisuke、Saito Takuro、Irie Takuma、Itahashi Kota、Minoura Kodai、Suzuki Susumu、Kojima Takashi、Kakimi Kazuhiro、Nakajima Jun、Funakoshi Takeru、Iida Shinsuke、Oka Mikio、Shimamura Teppei、Doi Toshihiko、Doki Yuichiro、Nakayama Eiichi、Ueda Ryuzo、Nishikawa Hiroyoshi
  • Journal Title: Nature Communications Volume: 12(1) Issue: 1 Pages: 7280-7280
  • DOI: 10.1038/s41467-021-27574-0
  • Peer Reviewed / Open Access
• [Journal Article] Highly immunogenic cancer cells require activation of the WNT pathway for immunological escape (2021)
  • Author(s): Takeuchi Y, Tanegashima T, Sato E, Irie T, Sai A, Itahashi K, Kumagai S, Tada Y, Togashi Y, Koyama S, Akbay EA, Karasaki T, Kataoka K, Funaki S, Shintani Y, Nagatomo I, Kida H, Ishii G, Miyoshi T, Aokage K, Kakimi K, Ogawa S, Okumura M, Eto M, Kumanogoh A, Tsuboi M, Nishikawa H
  • Journal Title: Science Immunology Volume: 6 Issue: 65
  • DOI: 10.1126/sciimmunol.abc6424
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] Integrated multiomics profiling identifies the differentiation program of regulatory T cells in human tumors (2022)
  • Author(s): Takuma Irie、Itahashi Kota、Yuda Junichiro、Kumagai Shogo、Tanegashima Tokiyoshi、Lin Yi-Tzu、Watanabe Sho、Goto Yasushi、Suzuki Jun、Aokage Keiju、Tsuboi Masahiro、Minami Yosuke、Ishii Genichiro、Ohe Yuichiro、Ise Wataru、Kurosaki Tomohiro、Suzuki Yutaka、Koyama Shohei、Nishikawa Hiroyoshi
  • Organizer: 第51回日本免疫学会学術集会
• [Book] シン・マクロファージ あらゆる疾患を制御する機能的多様性 (2022)
  • Author(s): 佐藤 荘
  • Total Pages: 211
  • Publisher: 羊土社
  • ISBN: 9784758104012