State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China.
Department of Medical Oncology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China.
J Clin Invest. 2019 Aug 13;129(11):4850-4862. doi: 10.1172/JCI127471.
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 (ICD)-inducing drugs available that can kill cancer cells, enhance tumor immunogenicity, increase the in vivo immune infiltration, and thereby boosting a tumor response to immunotherapy. So far, the ICD markers have been identified as the few immuno-stimulating characteristics of dead cells, but whether the presence of such ICD markers on tumor cells translates into enhanced antitumor immunity in vivo is still investigational. 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 T cell activation assay. We identified that teniposide, a DNA topoisomerase II inhibitor, could induce high mobility group box 1 (HMGB1) release and type I interferon signaling in tumor cells, and 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-κB activation and STING-dependent type I interferon signaling, both of which contribute to the activation of dendritic cells and subsequent T cells. Furthermore, teniposide potentiated the antitumor efficacy of anti-PD1 on multiple types of mouse tumor models. Our findings showed that teniposide could trigger tumor immunogenicity, and enabled a potential chemo-immunotherapeutic approach to potentiate the therapeutic efficacy of anti-PD1 immunotherapy.
检查点阻断抗体已被批准作为多种癌症的免疫疗法，但响应率和疗效仍然有限。目前可用的能够杀伤癌细胞、增强肿瘤免疫原性、增加体内免疫细胞浸润从而增强肿瘤对免疫治疗反应的免疫原性细胞死亡（ICD）诱导药物很少。到目前为止，ICD 标志物已被确定为死亡细胞中为数不多的免疫刺激特征，但肿瘤细胞上是否存在这种 ICD 标志物是否能转化为体内增强的抗肿瘤免疫仍在研究中。为了鉴定能够诱导肿瘤细胞死亡并增强 T 细胞反应的抗癌药物，我们基于 ICD 报告基因检测和 T 细胞激活检测进行了药物筛选。我们发现依托泊苷（一种 DNA 拓扑异构酶 II 抑制剂）能够诱导肿瘤细胞高迁移率族蛋白 B1（HMGB1）释放和 I 型干扰素信号通路，并且依托泊苷处理的肿瘤细胞能够在体外和体内激活抗肿瘤 T 细胞反应。在机制上，依托泊苷诱导肿瘤细胞 DNA 损伤和先天免疫信号通路，包括 NF-κB 激活和 STING 依赖性 I 型干扰素信号通路，这两者都有助于树突状细胞的激活和随后的 T 细胞激活。此外，依托泊苷增强了抗 PD-1 在多种小鼠肿瘤模型中的抗肿瘤疗效。我们的研究结果表明，依托泊苷能够触发肿瘤免疫原性，并为潜在的化疗免疫治疗方法提供了增强抗 PD-1 免疫治疗疗效的机会。
