结肠直肠癌有机体驱动低氧,TGF-β,以及NK细胞激活程序的患者特异多样化
Andreas von Kries1, Irene Garcés-Lázaro1, Bianca M Balzasch1
1Mannheim Institute for Innate Immunoscience (MI3), Universitätsmedizin Mannheim Medizinische Fakultät Mannheim, Mannheim, Germany.
自然杀手 (NK) 细胞在结直肠癌 (CRC) 免疫疗法方面表现有前途. 一个新的共同培养模型揭示了瘤微环境如何影响NK细胞,为个性化治疗铺平了道路.
科学领域:
- 免疫学 免疫学 免疫学
- 在瘤学瘤学.
- 遗传学 遗传学 是一个
背景情况:
- 结肠直肠癌 (CRC) 的异质性限制了T细胞免疫疗法的有效性.
- 自然杀手 (NK) 细胞是一种有前途的免疫疗法,但它们与瘤微环境的相互作用尚不清楚.
- 缺乏多样化的人类瘤模型阻碍了患者选择NK细胞疗法.
研究的目的:
- 建立一个共同培养平台,研究结直肠癌患者衍生器官 (PDO) 和NK细胞.
- 在CRC瘤微环境中研究NK细胞激活和抑制的分子机制.
- 确定增强结直肠癌NK细胞基础免疫疗法的策略.
主要方法:
- 基因多样化的结直肠癌患者衍生器官 (PDO) 与原发性NK细胞共同培养.
- 大量NK细胞RNA测序,流细胞计和IncuCyte活细胞成像.
- 测试CRISPR-Cas9编辑细胞,小分子和单克隆抗体,以增强NK细胞功能.
主要成果:
- 在共同培养中,NK细胞获得了缺氧和TGF-β转录特征,反映了体内CRC透.
- 观察到PDO对NK细胞杀死敏感性的患者特异性差异.
- 在PDOs上,MHC I类缺乏和NKG2D-连接体表达增强了NK细胞的细胞毒性和激活.
- 向HIF1A/EPAS1或TGF-βR1,或使用抗CEACAM1mAbs,改善NK细胞介导的杀死或激活.
结论:
- NK细胞/PDO共同培养平台确定了对NK细胞的常见和患者特定的瘤微环境影响.
- 这个平台可以指导个性化结直肠癌免疫疗法的开发.
- 大多数结肠直肠癌PDO (CMS2/CMS3) 对NK细胞杀伤敏感,表明了CRC中的NK细胞潜力.
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