腫瘍におけるADAR1の喪失は,免疫チェックポイントの阻害に対する抵抗を克服する
Jeffrey J Ishizuka1,2,3, Robert T Manguso1,3, Collins K Cheruiyot1,3
1Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
Nature
|December 19, 2018
まとめ
腫瘍細胞におけるRNA編集酵素ADAR1の喪失は,免疫療法に対する敏感性を高め,炎症を増加させることで,チェックポイント阻害に対する抵抗を克服します. この戦略はT細胞認識の必要性を回避する可能性がある.
科学分野:
- 免疫学
- 腫瘍学
- 分子生物学
背景:
- 多くのがん患者は免疫チェックポイントブロック (ICB) に反応せず,または抵抗性を発症します.
- 既得変異による抗原表現の障害は,ICB耐性の一般的な原因です.
- RNA編集は免疫刺激に対する細胞の反応を 調節する上で重要な役割を果たします
研究 の 目的:
- 免疫療法に対する腫瘍反応におけるRNA編集酵素ADAR1の役割を調査する.
- ADAR1機能の喪失がICBに対する抵抗を克服できるかどうかを判断する.
- ADAR1が抗腫瘍免疫に影響を与えるメカニズムを解明する.
主な方法:
- 腫瘍細胞におけるADAR1機能喪失の影響を研究した.
- インターフェロン誘導RNAのA-to-I編集レベルを分析した.
- PKRとMDA5経路の活性化を研究した.
- 腫瘍がPD-1のチェックポイントの ブロックに敏感になったと判断した
主要な成果:
- ADAR1の機能の喪失は 腫瘍を免疫療法に強く敏感にします
- ADAR1の活性が低下すると,インターフェロン誘導RNAのA-to- I編集が低下する.
- これはPKRとMDA5の活性化につながり,腫瘍の成長抑制と炎症を促進します.
- ADAR1の喪失は,抗原表現の障害によって引き起こされるPD-1阻害抵抗を克服する.
結論:
- ADAR1は,抗腫瘍免疫における先天性リガンド感知を制限する抑制チェックポイントとして作用する.
- ADAR1をターゲットにすることで,腫瘍を免疫療法に敏感にし,抵抗を克服することができます.
- ADAR1抑制による炎症誘発は,CD8+ T細胞認識の必要性を回避し,免疫療法に対する一般的な戦略を提供する.
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