Department of Molecular and Radiooncology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
Department of Medical Oncology, National Center for Tumor Diseases (NCT), Heidelberg, Germany.
Sci Adv. 2022 Mar 25;8(12):eabh4050. doi: 10.1126/sciadv.abh4050. Epub 2022 Mar 23.
Radiotherapy is a mainstay cancer therapy whose antitumor effects partially depend on T cell responses. However, the role of Natural Killer (NK) cells in radiotherapy remains unclear. Here, using a reverse translational approach, we show a central role of NK cells in the radiation-induced immune response involving a CXCL8/IL-8-dependent mechanism. In a randomized controlled pancreatic cancer trial, CXCL8 increased under radiotherapy, and NK cell positively correlated with prolonged overall survival. Accordingly, NK cells preferentially infiltrated irradiated pancreatic tumors and exhibited CD56-like cytotoxic transcriptomic states. In experimental models, NF-κB and mTOR orchestrated radiation-induced CXCL8 secretion from tumor cells with senescence features causing directional migration of CD56 NK cells, thus linking senescence-associated CXCL8 release to innate immune surveillance of human tumors. Moreover, combined high-dose radiotherapy and adoptive NK cell transfer improved tumor control over monotherapies in xenografted mice, suggesting NK cells combined with radiotherapy as a rational cancer treatment strategy.
放射疗法是一种主要的癌症治疗方法，其抗肿瘤作用部分取决于 T 细胞反应。然而，自然杀伤 (NK) 细胞在放射疗法中的作用尚不清楚。在这里，我们采用反向转化方法，显示了 NK 细胞在涉及 CXCL8/IL-8 依赖性机制的放射免疫反应中的核心作用。在一项随机对照的胰腺癌试验中，放射治疗下 CXCL8 增加，NK 细胞与延长的总生存期呈正相关。因此，NK 细胞优先浸润放射治疗的胰腺肿瘤，并表现出 CD56 样细胞毒性转录组状态。在实验模型中，NF-κB 和 mTOR 协调具有衰老特征的肿瘤细胞释放放射诱导的 CXCL8，导致 CD56NK 细胞的定向迁移，从而将衰老相关的 CXCL8 释放与人类肿瘤的固有免疫监视联系起来。此外，高剂量放射治疗和过继性 NK 细胞转移联合治疗在异种移植小鼠中改善了肿瘤控制，这表明 NK 细胞联合放射治疗是一种合理的癌症治疗策略。
