FLT3L Release by Natural Killer Cells Enhances Response to Radioimmunotherapy in Preclinical Models of HNSCC.
FLT3L Release by Natural Killer Cells Enhances Response to Radioimmunotherapy in Preclinical Models of HNSCC.
复制标题
DOI：
10.1158/1078-0432.ccr-21-0971
复制
发表时间：
2021-11-15
期刊：
影响因子：
--
通讯作者：
Karam SD
中科院分区：
文献类型：
--
作者：
Bickett TE;Knitz M;Darragh LB;Bhatia S;Van Court B;Gadwa J;Bhuvane S;Piper M;Nguyen D;Tu H;Lenz L;Clambey ET;Barry K;Karam SD
天然杀伤（NK）细胞是1型先天淋巴样细胞，已知可分泌细胞因子及其在杀死病毒感染细胞或癌细胞中的作用，通过直接细胞毒性。除了直接的肿瘤细胞杀伤外，NK细胞还通过分泌诸如FMS样细胞因子（例如FMS样酪氨酸激酶3配体）（FLT3L）的关键细胞因子的分泌在肿瘤微环境中起基本作用。尽管放射疗法（RT）是大多数癌症的主要治疗方法，但辐射疗法对NK细胞的作用尚未很好地表征。
这项研究结合了辐射，免疫疗法，遗传小鼠模型和抗体耗竭实验，以鉴定NK细胞在克服对RT的耐药性中的作用，在头颈鳞状细胞癌的正位模型中。
我们发现，NK细胞是抗肿瘤反应发展的关键组成部分，因为它们消除了它们消除了RT，抗CD25和抗CD137的先前成功组合处理的疗效。但是，在没有NK细胞的情况下，可以通过使用FLT3L处理来挽救效果。但是，单独使用FLT3L治疗的RT或抗NKG2A的RT都不会产生任何有意义的肿瘤生长延迟。我们还确定了IL-2在激活NK细胞分泌FLT3L中的作用。我们表明，该活性是通过CD122（中间亲和力IL-2受体）介导的，可以用抗CD25治疗靶向。
这些发现突出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中的重要性以增加肿瘤监测。
Natural Killer (NK) cells are type 1 innate lymphoid cells that are known to secrete cytokines and 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 radiation therapy (RT) is the mainstay treatment most cancers, the role of radiation therapy on NK cells is not well characterized. This study combines radiation, immunotherapies, genetic mouse models, and antibody depletion experiments to identify the role of NK cells in overcoming resistance to RT in orthotopic models of head and neck squamous cell carcinoma. We have found that NK cells are a crucial component in the development of an anti-tumor response, as depleting them removes efficacy of the previously successful combination treatment of RT, anti-CD25 and anti-CD137. However, in the absence of NK cells, the effect can be rescued through treatment with FLT3L. But neither RT with FLT3L therapy alone nor RT with anti-NKG2A yields any meaningful tumor growth delay. We also identify a role for IL-2 in activating NK cells to secrete FLT3L. This activity, we show, is mediated through CD122, the intermediate affinity IL-2 receptor and can be targeted with anti-CD25 therapy. 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.