VISTAはPSGL-1の酸性pH選択リガンドである
Robert J Johnston1, Linhui Julie Su2, Jason Pinckney3
1Immuno-Oncology Discovery, Bristol-Myers Squibb, Redwood City, CA, USA. robert.johnston@bms.com.
Nature
|October 25, 2019
まとめ
腫瘍の微小環境は,VISTAが酸性pHでPSGL-1に結合することでT細胞を抑制する. この相互作用を阻害すると,免疫抑制が逆転し,pHが
科学分野:
- 免疫学
- 癌 生物学
- 分子生物学
背景:
- CTLA-4やPD-1のような共抑制性免疫受容体は,がんにおけるT細胞機能障害に寄与する.
- CTLA- 4とPD- 1を標的とした現在の治療は有効だが,抗腫瘍免疫を完全に回復させるわけではない.
- 腫瘍が免疫抑制環境を作り出すメカニズムは完全に理解されていません.
研究 の 目的:
- 腫瘍の微小環境内のT細胞抑制におけるV領域の免疫グロブリン活性化抑制剤 (VISTA) の役割を調査する.
- VISTAによる免疫抑制を媒介する分子相互作用と環境要因を特定する.
- 抗腫瘍免疫を強化するための潜在的な治療標的としてVISTAを調査する.
主な方法:
- 異なるpH条件下でのT細胞とのVISTAの相互作用の特徴
- VISTA-PSGL-1結合に関与する主要なアミノ酸の残留物の特定
- 酸性環境でVISTA-PSGL-1の相互作用を標的としたブロック抗体の開発と試験
- VISTAによる免疫抑制の逆転における抗体の有効性のインビボ評価.
主要な成果:
- 腫瘍の微小環境の特徴である酸性pHで,VISTAは選択的にT細胞を活性化させ抑制する.
- VISTAの特定のヒスティジン残基は,P-セレクチングリコタンパク質リガンド-1 (PSGL-1) に結合する.
- 酸性条件下でVISTA- PSGL- 1の相互作用を阻害するように設計された抗体は,VISTAによる免疫抑制を in vivoで効果的に逆転させた.
結論:
- VISTAは,PSGL-1によるT細胞活動を抑制するために,腫瘍の微小環境の酸性pHを利用します.
- pHによって調節されるVISTA- PSGL- 1の相互作用は,腫瘍誘発免疫抵抗の新しいメカニズムを表しています.
- pHに依存するVISTA-PSGL-1軸をターゲットにすることで,がん治療における免疫回避を克服するための有望な戦略が提供されます.
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