腫瘍のインターフェロン信号は,免疫チェックポイントの阻害に対する多種性抵抗プログラムを調節する
Joseph L Benci1, Bihui Xu1, Yu Qiu1
1Department of Radiation Oncology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Abramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
Cell
|December 3, 2016
まとめ
長期間のインターフェロンシグナル伝達により PD1阻害のようながん免疫療法に対する耐性が生じます このシグナル伝達を阻害すると,抗腫瘍免疫が回復し,チェックポイント阻害剤に対する反応が改善されます.
科学分野:
- 免疫学
- 腫瘍学
- 分子生物学
背景:
- PD1経路を標的とした免疫チェックポイントブロック (ICB) 療法では,有意な抗腫瘍効果が示されています.
- しかし,ICBに対する耐性は,治療の成功を制限する一般的な臨床的課題です.
- 耐性メカニズムの理解は,がん免疫療法の成果を改善するために不可欠です.
研究 の 目的:
- インターフェロンシグナル伝達がICBと併用療法に対する抵抗を媒介する役割を調査する.
- インターフェロンによる抵抗に 関わる分子経路を特定する
- この抵抗を克服するための 治療戦略を探求すること
主な方法:
- 腫瘍サンプルとT細胞の分析
- インターフェロン信号伝達経路の遺伝子と薬学的操作
- 免疫療法に対するT細胞機能と腫瘍の反応の評価
主要な成果:
- I型およびII型インターフェロンシグナル伝達が長続きすると,ICBおよび併用療法に対するPDL1依存および独立した抵抗が促進される.
- インターフェロンのシグナリングは,STAT1に関連する表遺伝子変化を誘発し,抑制性受容体リガンドを上調する.
- インターフェロンのシグナル伝達を阻害すると,T細胞機能が回復し,耐性腫瘍はICB単独治療に敏感になる.
- インターフェロンによる耐性のバイオマーカーは,抗PD1療法後の臨床進行と相関しています.
結論:
- 腫瘍のインターフェロンシグナル伝達は,がんの免疫療法に対する適応抵抗性の主要な要因です.
- インターフェロン反応経路をターゲットにすることで,抵抗を克服し,抗腫瘍免疫を強化することができます.
- インターフェロンシグナル伝達を阻害することで,複合免疫療法の必要性を回避することがあります.
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