Elucidation of the mechanism of CD8+ T cell exhaustion in lung cancer

• Project/Area Number: 20K08531
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 53030:Respiratory medicine-related
• Research Institution: National Cancer Center Japan
• Principal Investigator: Nishinakamura Hitomi 国立研究開発法人国立がん研究センター, 研究所, 研究員 (90597692)
• Co-Investigator(Kenkyū-buntansha): 板橋 耕太 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 (10828990)
• Project Period (FY): 2020-04-01 – 2023-03-31
• Project Status: Completed (Fiscal Year 2022)
• Budget Amount: ¥4,030,000 (Direct Cost: ¥3,100,000、Indirect Cost: ¥930,000); Fiscal Year 2022: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2021: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2020: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000)
• Keywords: T細胞の活性化 / T細胞の疲弊化 / 転写因子 / 疲弊化 / 活性化 / 活性化と疲弊化 / 腫瘍免疫

Outline of Research at the Start

がん免疫療法ではがん細胞を特異的に攻撃できるCD8+T細胞が重要な役割を担う。しかし、CD8+T細胞が慢性的ながん抗原刺激により疲弊して機能不全になった場合には、免疫療法の効果が低下する。本研究では、非小細胞肺がんにおいて、ヒトCD8+T細胞が疲弊する分子機構を、転写因子TOX1およびTOX2の役割を明確にすることで解明する。疲弊化を制御する因子とその作用機序の解明はCD8+T細胞を標的とした有効的ながん免疫療法の開発に繋がる。

Outline of Final Research Achievements

Analysis of tumor infiltrating lymphocytes (TILs) from non-small cell lung cancer (NSCLC) specimens revealed that T-bet and Eomes are important for the activation of CD8-positive T cells. On the other hand, ATAC-seq and RNA-seq of NSCLC TILs revealed that the expression of transcription factors TOX1 and TOX2 was significantly higher in exhausted CD8-positive T cells than in naive CD8-positive T cells. Furthermore, scRNA-seq open data of lung cancer TILs showed that when CD8-positive T cells were exhausted, the expression of T-bet and EOMES was decreased and that of transcription factors TOX1 and TOX2 was increased significantly. These data suggested four representative transcription factors whose expression is significantly altered when CD8-positive T cells are activated or exhausted in human lung cancer.

Academic Significance and Societal Importance of the Research Achievements

免疫チェックポイント阻害薬である抗PD-1抗体を用いたがん治療の奏功率は20-30%に止まる。この効果を上げるために様々な薬剤との併用療法の開発が進んでいる。しかしながら腫瘍内のCD8陽性T細胞が活性化して疲弊化に至る際の転写因子の作用機序については不明な点が数多く残されている。ヒト検体の網羅的解析から発見した転写因子の関係性を明らかにすることでより実臨床へ還元することが可能な研究である。

Research Products

• [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] HLA Class I Analysis Provides Insight Into the Genetic and Epigenetic Background of Immune Evasion in Colorectal Cancer With High Microsatellite Instability (2022)
  • Author(s): Kawazu M, Ueno T, Saeki K, Sax N, Togashi Y, Kanaseki T, Chida K, Kishigami F, Sato K, Kojima S, Tanegashima T, Matsubara D, Tane K, Tanaka Y, Iinuma H, Hashiguchi Y, Hazama S, Khor SS, Tokunaga K, Tsuboi M, Niki T, Eto M, Shitara K, Torigoe T, Ishihara S, Aburatani H, Haeno H, Nishikawa H, Mano H
  • Journal Title: Gastroenterology Volume: 162 Issue: 3 Pages: 799-812
  • DOI: 10.1053/j.gastro.2021.10.010
  • Peer Reviewed / Open Access
• [Journal Article] The PD-1 expression balance between effector and regulatory T cells predicts the clinical efficacy of PD-1 blockade therapies (2020)
  • Author(s): Kumagai S,Togashi Y,Kamada T,Sugiyama E,Nishinakamura H,Takeuchi Y,Vitaly K,Itahashi K,Maeda Y,Matsui S,Shibahara T,Yamashita Y,Irie T,Tsuge A,Fukuoka S,Kawazoe A,Udagawa H,Kirita K,Aokage K,Ishii G,Kuwata T,Nakama K,Kawazu M,Ueno T,Yamazaki N,Goto K,Tsuboi M,Mano H,Doi T,Shitara K,Nishikawa H
  • Journal Title: Nature Immunology Volume: 21 Issue: 11 Pages: 1346-1358
  • DOI: 10.1038/s41590-020-0769-3
  • Peer Reviewed / Open Access