LRRC15+肌纤维细胞决定了抑制瘤免疫力的树突设定点
Akshay T Krishnamurty1, Justin A Shyer1, Minh Thai1
1Genentech, South San Francisco, CA, USA.
Nature
|September 28, 2022
概括
转化癌症治疗:通过抑制TGFβ来向含有白素的重复蛋白15 (LRRC15) + 与癌症相关的纤维细胞,可以增强抗瘤免疫力并改善免疫治疗反应.
科学领域:
- 癌症学
- 免疫学
- 细胞生物学
背景情况:
- 在人类和小鼠癌症中,单细胞研究显示含有白蛋白的重复蛋白15 (LRRC15) + 肌纤维细胞.
- 癌症相关纤维细胞 (CAFs) 的分子驱动因素和免疫影响在很大程度上是未知的.
研究的目的:
- 研究胰腺癌中LRRC15+CAFs的体内发育和功能.
- 确定LRRC15+CAFs在抗瘤免疫力和免疫检查点阻塞反应中的作用.
主要方法:
- 使用胰腺癌的小鼠模型.
- 使用遗传证据来确定TGFβ受体2型信号对于LRRC15+肌纤维细胞发育至关重要.
- 开发了Lrrc15-diphtheria毒素受体敲入小鼠用于选择性CAF耗尽.
主要成果:
- 皮肤上素+ 纤维细胞中的TGFβ受体2型信号驱动LRRC15+ CAF的发展.
- 对LRRC15+CAF的选择性消耗降低了瘤纤维细胞含量,并将组成转向通用纤维细胞.
- 通过抗PDL1疗法,CAF消耗增强了CD8+T细胞效应器功能,并增加了瘤回归.
结论:
- 通过抑制CD8+T细胞和限制免疫疗法的有效性,TGFβ依赖的LRRC15+CAF促进瘤生长.
- 向LRRC15+肌纤维细胞提供了一个潜在的策略,以恢复平稳的肌纤维细胞群,并改善癌症患者的结果和免疫治疗反应.
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