Myc通过编程炎症和免疫抑制与Ras合作
Roderik M Kortlever1, Nicole M Sodir1, Catherine H Wilson2
1Department of Biochemistry, University of Cambridge, 80 Tennis Court Road, Cambridge CB2 1GA, UK; Department of Pathology and Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA 94143, USA.
Cell
|December 2, 2017
概括
癌基因KRas和Myc通过重编程瘤微环境来驱动癌症. 阻断CCL9和IL-23的信号抑制了瘤的生长,揭示了治疗点.
科学领域:
- 癌症学
- 免疫学
- 分子生物学
背景情况:
- KRas和Myc瘤基因在瘤发生过程中合作.
- 在推动瘤进展方面,Kras- Myc合作的确切机制尚未完全理解.
- 了解瘤微环境的作用对于开发有效的癌症疗法至关重要.
研究的目的:
- 阐明KRas和Myc合作驱动瘤发生的机制.
- 确定瘤进展过程中的关键信号通路.
- 在KRas驱动的肺癌模型中评估向这些途径的治疗潜力.
主要方法:
- 使用KRasG12D驱动的小鼠肺癌模型.
- 研究了Myc联合激活对瘤生长,扩散和侵袭的影响.
- 分析了瘤层的组成和免疫格局.
- 鉴定和特征表皮衍生信号分子 (CCL9和IL-23) 负责树皮重编程.
- 评估了CCL9和IL-23联合阻断对瘤进展的影响.
- 检查了Myc失活对已存在的瘤和结构变化的影响.
- 评估T细胞和NK细胞在瘤回归中的作用.
主要成果:
- 在KRas驱动的腺瘤中,Myc的联合激活迅速促进了侵袭性腺癌的发展.
- 瘤进展的特征是炎症性,血管性和免疫抑制性肌瘤.
- 表皮衍生CCL9和IL-23被确定为驱动结构重编程的关键信号.
- CCL9调解巨细胞的招募,血管生成和PD- L1依赖的T细胞和B细胞的排斥.
- IL-23可以调节适应性T细胞和B细胞以及NK细胞的排斥.
- 同时阻断CCL9和IL-23,有效抑制Myc诱导的瘤进展.
- 在已形成的瘤中,Myc的失活会导致瘤变化的迅速逆转和瘤的回归.
- 在Myc失活后的瘤回归独立于CD4+CD8+T细胞,但依赖于NK细胞.
结论:
- Myc广泛重新编程瘤层, 创建免疫抑制环境, 这对于瘤的进展至关重要.
- 针对CCL9和IL-23代表了对KRas驱动的肺癌的有希望的治疗策略.
- 瘤基因与瘤微环境之间的相互作用对癌症的发展和进展至关重要.
- 在瘤信号停止后,NK细胞在瘤回归中发挥着重要作用.
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