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通过降低瘤TNF细胞毒性值来增加免疫治疗的影响

David W Vredevoogd¹, Thomas Kuilman¹, Maarten A Ligtenberg¹

¹Division of Molecular Oncology and Immunology, Oncode Institute, Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX, Amsterdam, the Netherlands.

|July 16, 2019

概括

需要新的策略来改善免疫检查点阻塞 (ICB) 治疗. 通过向瘤亡因子 (TNF) 途径,特别是TRAF2,通过促进亡并增强ICB的有效性,使瘤对免疫疗法敏感.

科学领域:

免疫学
癌症学
分子生物学

背景情况:

免疫检查点阻塞 (ICB) 治疗具有前景,但需要新的策略来提高疗效.
已知干扰素- (IFNγ) 途径会影响ICB反应,但与IFNγ无关的途径,如瘤亡因子 (TNF) 的理解较少.
在瘤中,有限的TNF抗瘤活性与ICB反应不佳相关.

研究的目的:

通过研究 IFNγ 独立的信号通路来确定增强 ICB 治疗的新目标.
探索TNF通路在瘤对ICB反应中的作用,并确定TNF敏感性的遗传修饰因子.

主要方法:

在缺少IFNγ受体的瘤细胞中使用全基因组CRISPR/ Cas9查,以确定对CD8 T细胞中介杀死敏感性的遗传修饰剂.
对临床数据的分析,以将TNF通路活性与瘤状态和ICB反应相关联.
功能性研究,以调查TRAF2剥离对TNF信号传递和瘤细胞亡的影响机制.

主要成果:

一个全基因组查确定了TNF途径的几个组成部分对ICB反应至关重要.
TRAF2被确定为一个关键的调节剂,其切除将TNF信号重定向到依赖RIPK1的亡.
失去TRAF2增强了cIAP抑制和ICB的有效性,显示出协同作用.

结论:

通过向TRAF2来降低TNF细胞毒性值可以使瘤对免疫治疗敏感.
对于改善ICB结果的组合疗法,TNF通路,特别是TRAF2是一个有前途的目标.
这项研究强调了向IFNγ独立通路的潜力,以克服对癌症免疫治疗的抵抗力.

关键词:

一个TNF 在TRAF 一个子免疫检查点封锁免疫疗法肺癌肺癌黑色素瘤

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