腫瘍TNF細胞毒性の値を下げることで免疫療法の効果を高める
David W Vredevoogd1, Thomas Kuilman1, Maarten A Ligtenberg1
1Division of Molecular Oncology and Immunology, Oncode Institute, Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX, Amsterdam, the Netherlands.
Cell
|July 16, 2019
まとめ
免疫チェックポイントブロック (ICB) 治療を改善するために新しい戦略が必要である. 腫瘍死因 (TNF) 経路,特にTRAF2を標的にすることで,アポトーシスを促進し,ICBの有効性を高めることで,免疫療法に対する腫瘍を敏感にします.
科学分野:
- 免疫学
- 腫瘍学
- 分子生物学
背景:
- 免疫チェックポイントブロック (ICB) 治療は有望ですが,有効性を高めるための新しい戦略が必要です.
- インターフェロン- ガンマ (IFNγ) 経路はICB応答に影響することが知られているが,腫瘍死滅因子 (TNF) などのIFNγ独立経路は理解されていない.
- 腫瘍における限られたTNF抗腫瘍活動は,ICBに対する弱い反応と相関しています.
研究 の 目的:
- IFNγ独立のシグナル伝達経路を調査することによって,ICB療法を強化するための新しい標的を特定する.
- ICBに対する腫瘍反応におけるTNF経路の役割を調査し,TNF感受性の遺伝的変異因子を特定する.
主な方法:
- ゲノム全体のCRISPR/ Cas9スクリーニングは,IFNγ受容体欠乏の腫瘍細胞で,CD8 T細胞媒介による殺戮に対する感受性の遺伝的変異因子を特定するために使用されました.
- TNF経路の活性と腫瘍の状態とICB応答を相関させるための臨床データの分析.
- TRAF2の消去がTNFシグナル伝達と腫瘍細胞のアポトーシスに影響するメカニズムを調査する機能的研究.
主要な成果:
- 全ゲノムスクリーンは,TNF経路のいくつかの構成要素をICB応答にとって重要なものとして特定した.
- TRAF2は,RIPK1依存のアポトーシスへのTNFシグナルをリダイレクトする,主要な調節因子として特定された.
- TRAF2の喪失は,cIAP阻害とICBの有効性を高め,相乗効果を示した.
結論:
- TRAF2を標的にしてTNF細胞毒性の値を下げることで,免疫療法に対する腫瘍を敏感にすることができる.
- TNF経路,特にTRAF2は,ICBの治療結果を改善するための有望な標的です.
- この研究は,がんの免疫療法に対する抵抗を克服するために,IFNγ独立経路をターゲットにする可能性を強調しています.
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