在基因复制的结肠癌转移中,TGFβ驱动免疫逃避
Daniele V F Tauriello1,2, Sergio Palomo-Ponce1,2, Diana Stork1
1Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, Baldiri i Reixac 10, 08028 Barcelona, Spain.
Nature
|February 15, 2018
概括
转化性结肠直肠癌治疗:针对TGFβ,而不仅仅是PD-1,释放T细胞免疫力以预防转移并提高晚期疾病的免疫疗法的有效性.
科学领域:
- 癌症学
- 免疫学
- 癌症生物学
背景情况:
- 转移性结肠直肠癌 (CRC) 具有显著的死亡风险,通常是由瘤微环境因素而不是流行突变驱动的.
- 在CRC中的主要不良结果预测因素包括T细胞透率低,T-助手1 (TH1) 活性降低,转化生长因子β (TGFβ) 水平升高.
研究的目的:
- 研究转移性结直肠癌中遗传变化与瘤微环境之间的相互作用.
- 在临床前CRC模型中评估针对TGFβ信号和PD-1/PD-L1免疫检查点的有效性.
主要方法:
- 在肠道干细胞中产生四重突变小鼠具有四个主要CRC突变的条件等位基因.
- 瘤特征分析,包括T细胞透和TGFβ通路激活.
- 对单独和组合的PD-1/ PD- L1阻断和TGFβ抑制的治疗反应的评估.
主要成果:
- 四重突变小鼠发生了类似于人类微卫星稳定的CRC的转移性瘤,其特征是T细胞排斥和TGFβ激活的层状瘤.
- 抑制PD- 1/ PD- L1的有效性有限,而TGFβ的抑制诱导了强大的细胞毒性T细胞反应,防止转移.
- 在已形成肝转移的小鼠中阻断TGFβ对抗PD-1/ PD- L1治疗的敏感性.
结论:
- 瘤微环境中的TGFβ增加是CRC免疫逃避的关键机制,促进T细胞排斥并阻碍TH1效应细胞的发展.
- 向TGFβ信号是一种有前途的治疗策略,用于克服免疫逃避并提高晚期结肠直肠癌的免疫疗效.
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