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研究发现降低肿瘤细胞毒性阈值可增强免疫治疗效果
作者:小柯机器人 发布时间:2019/7/30 16:21:02

荷兰癌症研究所Daniel S. Peeper课题组取得一项新突破。他们研究出通过降低肿瘤内肿瘤坏死因子(TNF)的细胞毒性阈值来增强免疫治疗效果。 2019年7月25日出版的《细胞》杂志发表了这项成果。

临床研究表明,肿瘤坏死因子(TNF)的抗肿瘤活性仅局限于基线肿瘤和ICB无响应肿瘤,这与其低丰度有关。该研究团队利用基因筛分,消融了TNF受体关联因子TRAF2,改变TNF信号通路,使其便于RIPK1依赖的凋亡,从而降低肿瘤肿瘤坏死因子的细胞毒性阈值。TRAF2的丢失,很大程度上增强了其相互作用伙伴cIAP(另外一个筛查热门)的药理抑制治疗潜力,从而与ICB结合进行治疗。他们的结果表明,选择性降低TNF细胞毒性阈值,可以提高肿瘤对免疫治疗的敏感性。

研究人员表示,需要新的机会来增加免疫检查点封锁(ICB)的好处。而干扰素(IFN)γ途径既内含免疫检查点封锁抵抗因素,同时也含有治疗的机会。对于与IFNγ无关的信号通路尚未系统地调查。全基因组CRISPR / Cas9筛查技术使得缺乏IFNγ受体的肿瘤细胞对CD8 T细胞清除变得敏感,揭示了几条很受欢迎的有关肿瘤坏死因子(TNF)的途径 。

附:英文原文

Title: Augmenting Immunotherapy Impact by Lowering Tumor TNF Cytotoxicity Threshold

Author: David W. Vredevoogd, Thomas Kuilman, Maarten A. Ligtenberg, Maarten Altelaar, Ton N. Schumacher, Daniel S. Peeper

Issue&Volume:Volume 178 Issue 3

Abstract: New opportunities are needed to increase immune checkpoint blockade (ICB) benefit. Whereas the interferon (IFN)γ pathway harbors both ICB resistance factors and therapeutic opportunities, this has not been systematically investigated for IFNγ-independent signaling routes. A genome-wide CRISPR/Cas9 screen to sensitize IFNγ receptor-deficient tumor cells to CD8 T cell elimination uncovered several hits mapping to the tumor necrosis factor (TNF) pathway. Clinically, we show that TNF antitumor activity is only limited in tumors at baseline and in ICB non-responders, correlating with its low abundance. Taking advantage of the genetic screen, we demonstrate that ablation of the top hit, TRAF2, lowers the TNF cytotoxicity threshold in tumors by redirecting TNF signaling to favor RIPK1-dependent apoptosis. TRAF2 loss greatly enhanced the therapeutic potential of pharmacologic inhibition of its interaction partner cIAP, another screen hit, thereby cooperating with ICB. Our results suggest that selective reduction of the TNF cytotoxicity threshold increases the susceptibility of tumors to immunotherapy.

DOI: https://doi.org/10.1016/j.cell.2019.06.014

Source: https://www.cell.com/cell/fulltext/S0092-8674(19)30677-4

期刊信息
Cell:《细胞》,创刊于1974年。隶属于细胞出版社,最新IF:36.216
官方网址:https://www.cell.com/