癌症免疫疗法必需基因的鉴定
Shashank J Patel1,2, Neville E Sanjana3,4, Rigel J Kishton1
1National Cancer Institute, National Institutes of Health (NIH), Bethesda, Maryland 20892, USA.
Nature
|August 8, 2017
概括
基因突变会影响癌细胞对T细胞免疫疗法的反应. 在临床前模型中,阿佩林受体 (APLNR) 功能丧失会损害CD8+ T细胞活性,从而降低免疫治疗的有效性.
科学领域:
- 癌症研究
- 免疫学
- 遗传学
背景情况:
- 身体基因突变可以影响癌细胞对T细胞免疫疗法的敏感性.
- 了解驱动抗性的遗传变化对于改善癌症治疗结果至关重要.
研究的目的:
- 识别功能丧失突变对T细胞免疫疗法的抵抗性.
- 阐明特定基因突变影响抗瘤免疫力的机制.
主要方法:
- 在人类黑色素瘤细胞中利用基因组规模的CRISPR-Cas9屏幕来识别对CD8+T细胞功能的关键基因.
- 使用各种癌细胞系和抗原验证候选基因.
- 使用小鼠模型研究了已识别的基因在免疫治疗反应中的作用.
主要成果:
- 参与抗原呈现和干扰素马信号的基因在查中显著丰富.
- 在免疫治疗不耐药的瘤中发现了APLNR (编码阿佩林受体) 的功能丧失突变.
- APLNR与JAK1相互作用,调节干扰素-反应,其损失会损害体内免疫疗法的有效性.
结论:
- 这项研究将 CD8+ T 细胞功能必需基因的丧失与癌症对免疫疗法的抵抗联系起来.
- APLNR突变可能是免疫疗法耐药性的机制.
- 针对或理解APLNR的作用可以为克服治疗不响应的策略提供信息.
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