NR4A転写因子は,固体腫瘍におけるCAR T細胞機能を制限する
Joyce Chen1,2,3,4, Isaac F López-Moyado5,6,7, Hyungseok Seo5
1Division of Signaling and Gene Expression, La Jolla Institute for Immunology, La Jolla, CA, USA. jchen@lji.org.
Nature
|March 1, 2019
まとめ
固体腫瘍を標的とするキメリック抗原受容体 (CAR) T細胞は,NR4A転写因子により機能不全する. これらのNR4A因子を抑制することで,CAR T細胞の機能を回復させ,がんの免疫療法を改善することができます.
科学分野:
- 免疫学
- 癌 生物学
- 分子生物学
背景:
- 化学抗原受容体 (CAR) T細胞は,B細胞の悪性腫瘍に対して有効だが,固体腫瘍に対してはそれほど有効ではない.
- 固体腫瘍におけるCAR T細胞機能障害は,慢性的な抗原刺激と抑制受容体のアップレギュレーションに関連しています.
- この低反応状態は,特異的な転写因子活性化経路を伴う.
研究 の 目的:
- 固体腫瘍におけるCAR T細胞の反応低下のメカニズムを調査する.
- CAR T細胞の機能障害に関与する重要な分子要素を特定する.
- 癌の免疫療法におけるCAR T細胞の有効性を高めるための新しい治療目標を探求する.
主な方法:
- ヒトのCD19反応性CAR T細胞をCD19+腫瘍を持つマウスモデルに移植する.
- 腫瘍浸透性リンパ球 (TIL) の遺伝子発現とクロマチンアクセシビリティの分析.
- NR4A転写因子トリプルノックアウトCAR T細胞の生成と評価
主要な成果:
- 腫瘍におけるCD8+ CAR T細胞と内生TIL細胞は,NR4A転写因子に関連した類似した遺伝子発現プロファイルを示した.
- NR4A転写因子は,がん患者および慢性感染症患者からのT細胞で高く表現されました.
- NR4AトリプルノックアウトCAR T細胞は腫瘍の回帰を促進し,生存期間を延長し,エフェクターT細胞のフェノタイプを示した.
結論:
- NR4A転写因子は,T細胞の過反応性において,細胞内にある重要な役割を果たします.
- NR4A抑制は,がんにおけるCAR T細胞機能障害を克服するための有望な戦略です.
- NR4A因子をターゲットにすることで,固体腫瘍に対するCAR T細胞治療の有効性が向上する可能性があります.
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