Temporal analysis of type 1 interferon activation in tumor cells following external beam radiotherapy or targeted radionuclide therapy.
Temporal analysis of type 1 interferon activation in tumor cells following external beam radiotherapy or targeted radionuclide therapy.
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DOI：
10.7150/thno.54881
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发表时间：
2021
期刊：
影响因子：
12.4
通讯作者：
Morris ZS
中科院分区：
文献类型：
--
作者：
Jagodinsky JC;Jin WJ;Bates AM;Hernandez R;Grudzinski JJ;Marsh IR;Chakravarty I;Arthur IS;Zangl LM;Brown RJ;Nystuen EJ;Emma SE;Kerr C;Carlson PM;Sriramaneni RN;Engle JW;Aluicio-Sarduy E;Barnhart TE;Le T;Kim K;Bednarz BP;Weichert JP;Patel RB;Morris ZS
原理：临床上对靶向放射性核素治疗（TRT）与免疫治疗相结合的兴趣正在增长。外照射放射治疗（EBRT）通过干扰素基因刺激因子（STING）激活1型干扰素（IFN 1）应答，这对其与免疫检查点阻断的治疗相互作用至关重要。然而，关于EBRT后IFN 1激活的时间过程或这是否可能由TRT源的衰变引起的知之甚少。研究方法：我们使用qPCR和western印迹检测了B78和B16黑色素瘤以及MOC 2头颈癌小鼠模型中的IFN 1应答和免疫易感性标志物的表达。对于TRT，我们使用螯合到NM 600的90 Y，NM 600是一种烷基磷酸胆碱类似物，在包括B78和MOC 2在内的肿瘤细胞中表现出选择性摄取和保留。结果如下：我们在所有细胞系中观察到显著的IFN 1活化，在所有剂量的RT后，B78、B16和MOC 2细胞系中的活化峰值分别发生在7、7和1天。这种效应是针刺依赖性的。选择的IFN应答基因在RT后14天保持上调。体外STING激动剂处理后的IFN 1活化与RT相同，表明细胞系之间的时程差异是由STING途径动力学介导的，而不是DNA损伤易感性。EBRT和TRT在B78和MOC 2肿瘤的体内递送导致相当的时间过程和IFN 1活化的幅度。在MOC 2模型中，与单药治疗和累积剂量等效组合EBRT和双重检查点阻断治疗相比，90 Y-NM 600和双重检查点阻断治疗的组合减少了肿瘤生长并延长了生存期。结论：我们报告了在多种小鼠肿瘤模型中放射后STING依赖性IFN 1应答的时间过程。我们显示TRT刺激IFN 1活化的潜力与EBRT观察到的相当，这可能对TRT与免疫疗法的治疗整合至关重要。
Rationale: Clinical interest in combining targeted radionuclide therapies (TRT) with immunotherapies is growing. External beam radiation therapy (EBRT) activates a type 1 interferon (IFN1) response mediated via stimulator of interferon genes (STING), and this is critical to its therapeutic interaction with immune checkpoint blockade. However, little is known about the time course of IFN1 activation after EBRT or whether this may be induced by decay of a TRT source. Methods: We examined the IFN1 response and expression of immune susceptibility markers in B78 and B16 melanomas and MOC2 head and neck cancer murine models using qPCR and western blot. For TRT, we used 90Y chelated to NM600, an alkylphosphocholine analog that exhibits selective uptake and retention in tumor cells including B78 and MOC2. Results: We observed significant IFN1 activation in all cell lines, with peak activation in B78, B16, and MOC2 cell lines occurring 7, 7, and 1 days, respectively, following RT for all doses. This effect was STING-dependent. Select IFN response genes remained upregulated at 14 days following RT. IFN1 activation following STING agonist treatment in vitro was identical to RT suggesting time course differences between cell lines were mediated by STING pathway kinetics and not DNA damage susceptibility. In vivo delivery of EBRT and TRT to B78 and MOC2 tumors resulted in a comparable time course and magnitude of IFN1 activation. In the MOC2 model, the combination of 90Y-NM600 and dual checkpoint blockade therapy reduced tumor growth and prolonged survival compared to single agent therapy and cumulative dose equivalent combination EBRT and dual checkpoint blockade therapy. Conclusions: We report the time course of the STING-dependent IFN1 response following radiation in multiple murine tumor models. We show the potential of TRT to stimulate IFN1 activation that is comparable to that observed with EBRT and this may be critical to the therapeutic integration of TRT with immunotherapies.