通过逃避免疫的循环氧基酶依赖性瘤生长
Santiago Zelenay1, Annemarthe G van der Veen1, Jan P Böttcher1
1Immunobiology Laboratory, The Francis Crick Institute, Lincoln's Inn Fields Laboratory, 44 Lincoln's Inn Fields, London WC2A 3LY, UK.
Cell
|September 8, 2015
概括
癌细胞通过产生前列腺素E2 (PGE2) 来逃避免疫攻击. 抑制循环氧化酶 (COX) 使瘤易受免疫控制,并增强抗癌疗法.
科学领域:
- 免疫学
- 癌症学
- 分子生物学
背景情况:
- 癌细胞,特别是黑色素瘤, 拥有逃避宿主抗瘤免疫反应的机制.
- 这种免疫规避的确切分子途径尚未完全阐明.
- 促进瘤的炎症和免疫抑制是癌症进展的关键因素.
研究的目的:
- 调查前列腺素E2 (PGE2) 在癌细胞中介免疫逃避中的作用.
- 确定向PGE2生产是否可以恢复抗瘤免疫力.
- 探索循环氧化酶 (COX) 抑制剂作为癌症免疫治疗的辅助剂的潜力.
主要方法:
- 使用基因工程小鼠模型的黑色素瘤 (Braf ((V600E) 和Nras ((G12D))),乳腺和结肠直肠癌.
- 在癌细胞中基因移除的环氧酶 (COX) 或前列腺素E合成酶.
- 分析了瘤免疫特征和炎症特征.
- 将小鼠数据与人类皮肤黑色素瘤活检进行比较.
- 在临床前模型中评估了COX抑制剂和抗PD-1阻断的协同作用.
主要成果:
- 免疫能力强的宿主中的瘤生长严重依赖于癌细胞的PGE2产生.
- 对COX或前列腺素E合成的基因切除使瘤对免疫控制敏感.
- 这种基因改造将瘤的炎症特征转移到抗癌免疫路径上.
- 在小鼠中观察到的依赖COX的炎症特征在人类黑色素瘤中保持.
- 在临床前研究中,抑制与抗PD-1阻断协同作用的COX可以消除瘤.
结论:
- 癌细胞产生的前列腺素E2 (PGE2) 是免疫抑制和瘤生长的关键媒介.
- 向循环氧化酶 (COX) 酶会破坏PGE2的产生,使瘤易受免疫监测.
- 在各个物种中保存的COX驱动的免疫逃避机制突显了它在癌症中的意义.
- COX 抑制剂是增强当前免疫疗法 (如抗PD-1 阻断剂) 治疗癌症的有希望的策略.
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