MICAとMICBの流出を抗体媒介で抑制すると,NK細胞主導の腫瘍免疫が促進される
Lucas Ferrari de Andrade1,2, Rong En Tay1,2, Deng Pan1,2
1Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, 450 Brookline Avenue, Boston, MA 02215, USA.
Science (New York, N.Y.)
|March 31, 2018
まとめ
新しい抗体はMICAとMICBタンパク質を標的にし,がん細胞がこれらの免疫タグの分子を放出するのを防ぐ. このアプローチはNK細胞の免疫を活性化し,腫瘍の成長と転移を抑制します.
科学分野:
- 免疫学
- 癌 生物学
- 治療用抗体設計
背景:
- MICAとMICBタンパク質は,多くのヒトがんによって発現されるストレス誘発リガンドである.
- これらのリガンドは,細胞毒性リンパ球の自然キラー群2D (NKG2D) 受容体を誘導し,癌細胞を排除するために標識します.
- 腫瘍はMICAとMICBを放出することで 免疫監視を回避し この認識経路を無効にします
研究 の 目的:
- 癌細胞からMICAとMICBのタンパク質分解を防ぐ抗体を設計する.
- 臨床前モデルの腫瘍の成長と転移を抑制するこれらの抗体の有効性を評価する.
- 抗体媒介による抗腫瘍免疫反応の背後にあるメカニズムを解明する.
主な方法:
- タンパク質分解の重要な部位であるMICA α3ドメインを標的とした抗体の合理的な設計.
- がん細胞からMICA/MICBの流出を防止する抗体によるインビトロ評価
- 免疫能力のあるマウスモデルとメラノーマ転移のヒト化されたマウスモデルにおける抗体の有効性のインビオ試験.
- NKG2DおよびCD16Fc受容体による自然殺虫細胞 (NK) を含む免疫細胞の活性化の分析
主要な成果:
- 抗体はヒトの癌細胞による細胞表面MICAとMICBの脱落を成功裏に阻止した.
- これらの抗体による治療は,複数のマウスモデルで腫瘍の成長を有意に抑制しました.
- ヒトのメラノーマの拡大をマウスモデルで抑制した.
- 抗腫瘍免疫は主にNK細胞によってNKG2DおよびCD16受容体の活性化によって媒介された.
結論:
- 合理的に設計された抗体でMICA α3ドメインを標的にすることは,がんの免疫回避を防ぐために実行可能な戦略です.
- この治療法により,NKG2D媒介の抗腫瘍免疫が再活性化され,リガンドの脱落が防止されます.
- 開発された抗体は,MICA/MICBの流出によって免疫検出を回避するがんの治療に有意義な可能性を示しています.
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