美国西南医学中心Anli Zhang研究团队发现，端粒应力增强STING依赖的抗肿瘤免疫。2020年7月2日，《癌细胞》在线发表了这项成果。

研究人员发现端粒酶靶向药物6-thio-2'-脱氧鸟苷（6-thio-dG），可以通过先天性和适应性免疫依赖的应答使表达同源和人源化端粒酶的小鼠肿瘤消退。6-硫代-dG处理细胞导致端粒相关DNA损伤产生，其可被树突状细胞（DC）感知并激活宿主胞质DNA识别通路STING /干扰素I，从而导致DC交叉启动能力增强和肿瘤特异性CD8 ⁺ T细胞的激活。

此外,6-硫代-dG克服了晚期癌症模型中对检查点封锁的抵抗。该研究结果揭示了端粒应激如何增强先天性和适应性抗肿瘤免疫，并为靶向端粒与免疫治疗相结合的方法提供了有力支撑。

研究人员表示，端粒酶是抗肿瘤治疗的明星靶点，因为它几乎普遍在癌细胞中表达。

附：英文原文

Title: Telomere Stress Potentiates STING-Dependent Anti-tumor Immunity

Author: Ilgen Mender, Anli Zhang, Zhenhua Ren, Chuanhui Han, Yafang Deng, Silvia Siteni, Huiyu Li, Jiankun Zhu, Aishwarya Vemula, Jerry W. Shay, Yang-Xin Fu

Issue&Volume: 2020-07-02

Abstract: Telomerase is an attractive target for anti-tumor therapy as it is almost universallyexpressed in cancer cells. Here, we show that treatment with a telomere-targetingdrug, 6-thio-2′-deoxyguanosine (6-thio-dG), leads to tumor regression through innateand adaptive immune-dependent responses in syngeneic and humanized mouse models oftelomerase-expressing cancers. 6-thio-dG treatment causes telomere-associated DNAdamages that are sensed by dendritic cells (DCs) and activates the host cytosolicDNA sensing STING/interferon I pathway, resulting in enhanced cross-priming capacityof DCs and tumor-specific CD8+ T cell activation. Moreover, 6-thio-dG overcomes resistance to checkpoint blockadein advanced cancer models. Our results unveil how telomere stress increases innatesensing and adaptive anti-tumor immunity and provide strong rationales for combiningtelomere-targeting therapy with immunotherapy.

DOI: 10.1016/j.ccell.2020.05.020

Source: https://www.cell.com/cancer-cell/fulltext/S1535-6108(20)30270-1