癌の免疫療法に不可欠な遺伝子の特定
Shashank J Patel1,2, Neville E Sanjana3,4, Rigel J Kishton1
1National Cancer Institute, National Institutes of Health (NIH), Bethesda, Maryland 20892, USA.
Nature
|August 8, 2017
まとめ
遺伝子変異はT細胞免疫療法に対する癌細胞の反応に影響します. アペリン受容体 (APLNR) の機能の喪失は,CD8+ T細胞の活性を低下させ,臨床前モデルでは免疫療法の有効性を低下させる.
科学分野:
- 癌の研究
- 免疫学
- 遺伝学
背景:
- ソマティック遺伝子変異はT細胞免疫療法に対するがん細胞の感受性に影響を与える.
- 耐性を引き起こす遺伝子の変化を理解することは 癌治療の成果を改善するために不可欠です
研究 の 目的:
- T細胞免疫療法に対する抵抗性を与える機能喪失変異を有する遺伝子を特定する.
- 特定の遺伝子変異が抗腫瘍免疫に影響するメカニズムを解明する.
主な方法:
- ヒトのメラノーマ細胞におけるゲノムスケールのCRISPR-Cas9スクリーンを利用して,CD8+T細胞エフェクタ機能に重要な遺伝子を特定した.
- 様々ながん細胞系と抗原を用いて候補遺伝子を検証した.
- マウスモデルを用いて免疫療法の反応における特定された遺伝子の役割を調査した.
主要な成果:
- 抗原表現とインターフェロンガンマシグナル伝達に関与する遺伝子は,スクリーンで有意に濃縮された.
- APLNR (アペリン受容体をコードする) の機能喪失変異は,免疫療法に抵抗する腫瘍で確認された.
- APLNRはJAK1と相互作用し,インターフェロン-ガンマ応答を調節し,その喪失はインビオの免疫療法の有効性を損なう.
結論:
- この研究は,CD8+ T細胞機能に不可欠な遺伝子の喪失と,がんの免疫療法への抵抗を関連付けています.
- APLNR変異は,免疫療法に対する抵抗性の潜在的なメカニズムを表しています.
- APLNRの役割の標的化や理解は,治療への反応不良を克服するための戦略を導くことができます.
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