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ガン細胞に勝てるように腫瘍関連マクロファージを再プログラムする
Xian Zhang1, Shun Li1, Isha Malik1
1Immunology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
Nature
|June 28, 2023
まとめ
食事の変化によって 免疫細胞ががんと戦うように 再プログラムできます 低タンパク質のダイエットは,腫瘍関連マクロファージ (TAM) を活性化させ,MYC過剰発現するがん細胞に,mTORC1の信号伝達を阻害することで,新しい免疫抑制経路を明らかにします.
科学分野:
- 免疫学
- 癌 生物学
- メタボリズム
背景:
- 細胞の競争はメタゾーンにおける品質管理メカニズムですが,癌細胞によって併用されることがあります.
- 腫瘍マイクロ環境には,腫瘍関連マクロファージ (TAM) のような癌細胞とストロマが含まれています.
- 癌細胞の競争に影響を与える環境要因はよく理解されていません.
研究 の 目的:
- 環境要因,特に食生活が癌細胞の競争にどのように影響するか調べる.
- ガン細胞の競争を媒介する TAM の役割を決定する.
- 癌抑制のための新しい治療標的を特定する.
主な方法:
- MYC過剰発現細胞のマウスモデルを使用しました.
- 食事中のタンパク質のレベルを操作する (低タンパク質対正常タンパク質の食事).
- 重要なシグナルタンパク質 (GATOR1,FLCN,Rag GTPases,PIKfyve) を枯渇させる 遺伝子組み換え TAM
- mTORC1のシグナル伝達,TFEB/TFE3の活性化,腫瘍の成長の動態を評価した.
主要な成果:
- MYCの過剰発現は,mTORC1に依存する"勝者"の癌細胞状態を生み出しました.
- 低タンパク質の食事は癌細胞のmTORC1を抑制したが,TAMsのTFEB,TFE3,mTORC1を活性化し,腫瘍の成長を減少させた.
- TAMsにおけるGATOR1の減少は,低タンパク質食による抑制を阻害し,FLCNまたはRag GTPasesの減少は,通常の食による抑制を模倣した.
- PIKfyveは,TAMとがん細胞のmTORC1過剰活性化を媒介し,競争力に影響を与えた.
結論:
- TAMは食事によって再プログラムされ 癌細胞に勝てます
- TAMsにおける非正規の,吸収媒介の,Rag GTPase独立のmTORC1シグナリングは,細胞間競争を制御する.
- これは治療の可能性のある 免疫腫瘍抑制の新たな経路を表しています
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