De novo necroptosis creates an inflammatory environment mediating tumor susceptibility to immune checkpoint inhibitors.
De novo necroptosis creates an inflammatory environment mediating tumor susceptibility to immune checkpoint inhibitors.
复制标题
新生坏死性凋亡产生炎症环境，介导肿瘤对免疫检查点抑制剂的易感性。
DOI：
10.1038/s42003-020-01362-w
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发表时间：
2020-11-04
影响因子：
5.9
通讯作者：
Mossman KL
中科院分区：
文献类型：
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作者：
Workenhe ST;Nguyen A;Bakhshinyan D;Wei J;Hare DN;MacNeill KL;Wan Y;Oberst A;Bramson JL;Nasir JA;Vito A;El-Sayes N;Singh SK;McArthur AG;Mossman KL
使用单克隆抗体阻断抑制性检查点的癌症免疫疗法在许多类型的癌症患者中显示出持久的缓解，尽管大多数乳腺癌患者几乎没有获益。人类黑色素瘤和肺癌患者研究表明，免疫检查点抑制剂通常对已经有肿瘤内T细胞浸润的患者有效;尽管目前尚不清楚什么类型的干预措施会导致乳腺癌中的肿瘤内T细胞浸润。使用非T细胞发炎的乳腺肿瘤，我们评估了哪些生物过程和下游炎症可以克服自发T细胞引发的障碍。在这里，我们展示了一种特定类型的联合治疗，包括溶瘤病毒和化疗，激活坏死性凋亡和限制肿瘤生长的原位肿瘤。联合治疗激活促炎性细胞因子;髓样细胞的瘤内流入和局部治疗和远处原发肿瘤中的细胞毒性T细胞浸润，使其对免疫检查点抑制剂敏感。Workenhe等人在小鼠中表明，溶瘤HSV-1病毒和丝裂霉素-C的组合通过坏死性凋亡诱导激活炎症反应，使肿瘤对免疫检查点抑制剂敏感。这些发现揭示了坏死性凋亡在免疫治疗方法中的潜在作用。
Cancer immunotherapies using monoclonal antibodies to block inhibitory checkpoints are showing durable remissions in many types of cancer patients, although the majority of breast cancer patients acquire little benefit. Human melanoma and lung cancer patient studies suggest that immune checkpoint inhibitors are often potent in patients that already have intratumoral T cell infiltrate; although it remains unknown what types of interventions can result in an intratumoral T cell infiltrate in breast cancer. Using non-T cell-inflamed mammary tumors, we assessed what biological processes and downstream inflammation can overcome the barriers to spontaneous T cell priming. Here we show a specific type of combination therapy, consisting of oncolytic virus and chemotherapy, activates necroptosis and limits tumor growth in autochthonous tumors. Combination therapy activates proinflammatory cytokines; intratumoral influx of myeloid cells and cytotoxic T cell infiltrate in locally treated and distant autochthonous tumors to render them susceptible to immune checkpoint inhibitors. Workenhe et al. show in mice that a combination of oncolytic HSV-1 virus and Mitomycin-C activates an inflammatory response, through necroptosis induction, that renders tumours susceptible to immune checkpoint inhibitors. These findings informs on the potential role of necroptosis in immunotherapy approaches.