自然 の 殺人 細胞 は,成長 因子 を 感知 する こと に よっ て 腫瘍 の 成長 を 制御 する
Alexander D Barrow1, Melissa A Edeling1, Vladimir Trifonov2
1Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA.
Cell
|December 26, 2017
まとめ
血小板由来成長因子 (PDGF) -DDは腫瘍の成長を促しますが,NKp44による自然キラー細胞の認識は,抗腫瘍免疫反応を誘発します. この相互作用はサイトカインの放出と腫瘍細胞の成長停止につながり,潜在的な治療標的となる.
科学分野:
- 免疫学
- 腫瘍学
- 分子生物学
背景:
- 腫瘍はしばしば血小板由来成長因子 (PDGF-DD) を生成し,PDGFRβシグナル伝達によってがんの進行を促します.
- このシグナル伝達経路は細胞増殖,上皮-メゼンキマ移行,ストロマ反応,血管新生を促進する.
研究 の 目的:
- PDGF-DDと免疫細胞の相互作用を調査する.
- この相互作用が抗腫瘍免疫に及ぼす機能的影響を決定する.
主な方法:
- PDGF-DDのバインディングパートナーを特定するために,シークレトームライブラリをスクリーニングする.
- PDGF-DDの関与時のNK細胞活性化とサイトカイン生成の分析
- 遺伝子発現シグネチャとNKp44 (NCR2) 発現と患者生存の相関
- 腫瘍のコントロールを評価するためにマウスモデルを用いた in vivo 研究.
主要な成果:
- NK細胞に発現する免疫受容体NKp44は,PDGF-DDの受容体として特定されました.
- PDGF-DDによるNKp44の活性化により,NK細胞はインターフェロンガンマ (IFN-γ) と腫瘍死滅因子アルファ (TNF-α) を分泌する.
- これらの分泌されるサイトカインは 腫瘍細胞の成長停止を誘導します
- 特定の転写シグネチャーと相関し,グリブラストーマ患者の生存率を向上させた.
- NKp44を発現するNK細胞は,マウスのPDGF-DDを発現する腫瘍に対する制御が強化され,CD96阻害またはCpGオリゴヌクレオチド治療によりさらに改善された.
結論:
- 腫瘍に由来するPDGF-DDは,腫瘍の成長を促す一方で,NKp44を通じて先天的な免疫反応を活性化します.
- NK細胞のNKp44媒介信号は,抗腫瘍サイトカインの放出と成長停止を誘発する.
- この経路は,PDGF-DDを発現する腫瘍に対する先天的な免疫を活用することによって,潜在的な治療戦略を表しています.
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