cGAS/STING axis mediates a topoisomerase II inhibitor induced tumor immunogenicity
cGAS/STING axis mediates a topoisomerase II inhibitor induced tumor immunogenicity
复制标题
cGAS/STING 轴介导拓扑异构酶 II 抑制剂诱导的肿瘤免疫原性
DOI：
10.1172/jci127471
复制
发表时间：
2019-11-01
影响因子：
15.9
通讯作者：
Xia, Xiaojun
中科院分区：
文献类型：
--
作者：
Wang, Zining;Chen, Jiemin;Xia, Xiaojun
检查点阻断抗体已被批准用于多种类型癌症的免疫疗法，但缓解率和疗效仍然有限。很少有免疫原性细胞死亡诱导（ICD诱导）药物能够杀死癌细胞、增强肿瘤免疫原性、增加体内免疫浸润，从而增强肿瘤对免疫治疗的反应。迄今为止，ICD标记已被确定为死细胞的少数免疫刺激特征，但肿瘤细胞上此类ICD标记的存在是否会转化为体内抗肿瘤免疫力的增强仍在研究中。为了识别可诱导肿瘤细胞死亡和增强 T 细胞反应的抗癌药物，我们基于 ICD 报告基因测定和 T 细胞激活测定进行了药物筛选。我们发现，替尼泊苷（一种 DNA 拓扑异构酶 II 抑制剂）可以诱导肿瘤细胞中高迁移率族盒 1 (HMGB1) 释放和 I 型 IFN 信号传导，并且替尼泊苷处理的肿瘤细胞可以在体外和体内激活抗肿瘤 T 细胞反应。从机制上讲，替尼泊苷诱导肿瘤细胞 DNA 损伤和先天免疫信号传导，包括 NF-kappa B 激活和 IFN 基因依赖性（STING 依赖性）I 型 IFN 信号传导的刺激物，这两者都有助于激活树突状细胞和随后的 T 细胞。此外，替尼泊苷增强了抗 PD1 在多种小鼠肿瘤模型中的抗肿瘤功效。我们的研究结果表明，替尼泊苷可以触发肿瘤免疫原性，并成为一种潜在的化学免疫治疗方法，以增强抗 PD1 免疫疗法的治疗效果。
Checkpoint blockade antibodies have been approved as immunotherapy for multiple types of cancer, but the response rate and efficacy are still limited. There are few immunogenic cell death-inducing (ICD-inducing) drugs available that can kill cancer cells, enhance tumor immunogenicity, increase in vivo immune infiltration, and thereby boost a tumor response to immunotherapy. So far, the ICD markers have been identified as the few immunostimulating characteristics of dead cells, but whether the presence of such ICD markers on tumor cells translates into enhanced antitumor immunity in vivo is still being investigated. To identify anticancer drugs that could induce tumor cell death and boost T cell response, we performed drug screenings based on both an ICD reporter assay and a T cell activation assay. We showed that teniposide, a DNA topoisomerase II inhibitor, could induce high-mobility group box 1 (HMGB1) release and type I IFN signaling in tumor cells and that teniposide-treated tumor cells could activate antitumor T cell response both in vitro and in vivo. Mechanistically, teniposide induced tumor cell DNA damage and innate immune signaling, including NF-kappa B activation and stimulator of IFN genes-dependent (STING-dependent) type I IFN signaling, both of which contribute to the activation of dendritic cells and subsequent T cells. Furthermore, teniposide potentiated the antitumor efficacy of anti-PD1 in multiple types of mouse tumor models. Our findings showed that teniposide could trigger tumor immunogenicity and enabled a potential chemoimmunotherapeutic approach to potentiating the therapeutic efficacy of anti-PD1 immunotherapy.