CAR T細胞破壊は,固体ではなく液体腫瘍におけるIFNγR経路を必要とします
Rebecca C Larson1,2,3,4, Michael C Kann1,3, Stefanie R Bailey1,2,3
1Cellular Immunotherapy Program, Cancer Center, Massachusetts General Hospital, Boston, MA, USA.
Nature
|April 14, 2022
まとめ
化学抗原受容体 (CAR) T細胞治療は,血液がんに対して有効ですが,固体腫瘍に対しては有効ではありません. 耐性経路を発見した研究者は,インターフェロン・ガンマ受容体 (IFNγR) のシグナル伝達が,CAR T細胞が固体腫瘍細胞を殺すのに不可欠であることを発見した.
科学分野:
- 腫瘍学
- 免疫療法
- ゲノミクス
背景:
- 化学抗原受容体 (CAR) T細胞治療は 血液学的悪性腫瘍の治療に革命をもたらしました
- しかし,固体腫瘍に対する有効性は,潜在的内在抵抗性メカニズムのために限られている.
研究 の 目的:
- 固体腫瘍における耐性経路を ゲノム全体の CRISPR ノックアウトスクリーンを用いて 体系的に特定する
- インターフェロン・ガンマ受容体 (IFNγR) の信号伝達の作用を研究する.
主な方法:
- グリオブラストーマ細胞の全ゲノムCRISPRノックアウトスクリーンを実施した.
- 評価されたCAR T細胞細胞毒性 in vitroおよびin vivo.
- 細胞の反応を分析するために 転写プロフィールを使用した.
主要な成果:
- IFNγRシグナル伝達遺伝子の喪失 (IFNGR1,JAK1,JAK2) は,固体腫瘍におけるCAR T細胞に対する耐性を授与したが,血液学的悪性腫瘍には耐性を授与しなかった.
- IFNγR1欠乏した膠芽細胞は,細胞結合経路のアップレギュレーションが低下し,CAR T細胞の結合が低下した.
- IFNγRのシグナル伝達は,CAR T細胞の結合とグリブロスタモにおける生産性サイト毒性にとって不可欠である.
結論:
- 固体腫瘍と液体腫瘍は,CAR T細胞との相互作用によって異なります.
- IFNγRのシグナル伝達は,従来の抗原表現とは無関係に,固体腫瘍におけるCAR T細胞の感受性において極めて重要です.
- CAR T細胞結合相互作用の強化は,固体腫瘍の治療結果を改善する可能性があります.
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