Purpose: Natural killer (NK) cells are type I innate lymphoid cells that are known for their role in killing virally infected cells or cancer cells through direct cytotoxicity. In addition to direct tumor cell killing, NK cells are known to play fundamental roles in the tumor microenvironment through secretion of key cytokines, such as FMS-like tyrosine kinase 3 ligand (FLT3L). Although radiotherapy is the mainstay treatment in most cancers, the role of radiotherapy on NK cells is not well characterized. Experimental Design: This study combines radiation, immunotherapies, genetic mouse models, and antibody depletion experiments to identify the role of NK cells in overcoming resistance to radiotherapy in orthotopic models of head and neck squamous cell carcinoma. Results: We have found that NK cells are a crucial component in the development of an antitumor response, as depleting them removes efficacy of the previously successful combination treatment of radiotherapy, anti-CD25, and anti-CD137. However, in the absence of NK cells, the effect can be rescued through treatment with FLT3L. But neither radiotherapy with FLT3L therapy alone nor radiotherapy with anti-NKG2A yields any meaningful tumor growth delay. We also identify a role for IL2 in activating NK cells to secrete FLT3L. This activity, we show, is mediated through CD122, the intermediate affinity IL2 receptor, and can be targeted with anti-CD25 therapy. Conclusions: These findings highlight the complexity of using radio-immunotherapies to activate NK cells within the tumor microenvironment, and the importance of NK cells in activating dendritic cells for increased tumor surveillance.

中文翻译：

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自然杀伤细胞释放的 FLT3L 增强 HNSCC 临床前模型对放射免疫治疗的反应

目的：自然杀伤 (NK) 细胞是 I 型先天淋巴细胞，以其通过直接细胞毒性杀死病毒感染细胞或癌细胞的作用而闻名。除了直接杀伤肿瘤细胞外，NK 细胞还通过分泌关键细胞因子（例如 FMS 样酪氨酸激酶 3 配体 (FLT3L)）在肿瘤微环境中发挥重要作用。尽管放射治疗是大多数癌症的主要治疗方法，但放射治疗对 NK 细胞的作用尚不清楚。实验设计：本研究结合了放射、免疫疗法、遗传小鼠模型和抗体耗竭实验，以确定 NK 细胞在克服头颈鳞状细胞癌原位模型中放疗耐药性中的作用。结果：我们发现 NK 细胞是抗肿瘤反应发展的关键组成部分，因为耗尽它们会消除先前成功的放疗、抗 CD25 和抗 CD137 联合治疗的功效。然而，在缺乏 NK 细胞的情况下，可以通过 FLT3L 治疗来挽救这种效果。但单独使用 FLT3L 疗法的放射疗法或使用抗 NKG2A 疗法的放射疗法都不会产生任何有意义的肿瘤生长延迟。我们还确定了 IL2 在激活 NK 细胞分泌 FLT3L 中的作用。我们证明，这种活性是通过 CD122（中等亲和力 IL2 受体）介导的，并且可以通过抗 CD25 治疗来靶向。结论：这些发现强调了使用放射免疫疗法激活肿瘤微环境中 NK 细胞的复杂性，以及 NK 细胞在激活树突状细胞以增强肿瘤监测方面的重要性。