乳酸による腫瘍浸透調節性T細胞の代謝支援

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McLane J Watson^1,2,3, Paolo D A Vignali^1,2,3, Steven J Mullett⁴

¹Department of Immunology, University of Pittsburgh, Pittsburgh, PA, USA.

|February 16, 2021

まとめ

調節性T (Treg) 細胞は,乳酸のような代替代謝経路を使用して,腫瘍内の免疫抑制を維持します. Treg細胞における乳酸代謝をターゲットにすることで,腫瘍の成長を遅らせ,免疫療法の反応を高めます.

科学分野:

免疫学
癌生物学
代謝に関する研究

背景:

調節性T細胞は免疫ホメオスタシスに不可欠ですが,抗がん免疫を阻害します.
腫瘍の微小環境 (TME) はTレグ細胞の活動を促進し,代謝を変化させ,エフェクターT細胞にとって敵対的な環境を作り出します.
TME代謝とTreg細胞の機能との関連性を示唆する特異な代謝プロファイルを有する.

研究の目的:

TME内のTreg細胞の代謝の柔軟性を調査する.
機能と増殖を維持するために,Treg細胞が代替代謝経路を利用するかどうかを判断する.
ガンにおけるTreg細胞代謝を標的とした治療の可能性を調査する.

主な方法:

トレグ細胞のグルコース代謝の異質性の分析
高グルコースと高乳酸の条件下でのTreg細胞機能に関するインビトロ研究.
Treg細胞における乳酸媒介体MCT1の遺伝的消去
腫瘍の成長と免疫療法への反応の評価 in vivo

主要な成果:

Treg細胞は,抑制機能と増殖を維持するために乳酸を利用して,代謝の柔軟性を発揮します.
高血糖はTreg細胞の安定性を低下させ,乳酸はTreg細胞の機能と増殖を支える.
MCT1による乳酸の吸収は,腫瘍内Treg細胞の機能に不可欠です.
Treg細胞におけるMCT1の除去は腫瘍の成長を遅らせ,免疫療法の有効性を改善する.

結論:

Treg細胞は,その抑制的アイデンティティを代謝的にサポートすることによって,TMEに適応します.
腫瘍は免疫破壊を回避するメカニズムとして Treg細胞の代謝支援を利用します
Treg細胞の乳酸代謝をターゲットにすることは,抗癌免疫と免疫療法を強化するための有望な戦略です.

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