Adrenergic stress constrains the development of anti-tumor immunity and abscopal responses following local radiation
Adrenergic stress constrains the development of anti-tumor immunity and abscopal responses following local radiation
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DOI：
10.1038/s41467-020-15676-0
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发表时间：
2020-04-14
影响因子：
16.6
通讯作者：
Repasky, Elizabeth A.
中科院分区：
文献类型：
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作者：
Chen, Minhui;Qiao, Guanxi;Repasky, Elizabeth A.
电离放射治疗（RT）后的超视距效应被认为是一个罕见的事件。当与其他疗法（包括免疫疗法）联合使用时，这种效果确实会更频繁地发生。在这里，我们证明单纯放疗后体外事件的频率高度依赖于荷瘤宿主的肾上腺素能应激程度。结合生理、药理学和遗传策略，我们观察到当肾上腺素能应激或通过β -肾上腺素能受体的信号减少时，辐照和未辐照的远处肿瘤（包括转移性肿瘤）的控制都有所改善。此外，我们观察到细胞和分子证据的改善，抗原特异性，抗肿瘤免疫反应也依赖于T细胞从引流淋巴结的出口。这些数据表明，阻断β 2肾上腺素能应激信号可能是一种有效、安全、可行的策略，可以提高接受放射治疗的癌症患者的疗效。放射治疗后患者和临床前模型的抽象化反应是罕见的。本文作者表明，在小鼠肿瘤模型中，减少肾上腺素能应激或β 2-肾上腺素能受体信号不仅可以改善对辐照肿瘤的控制，还可以显著增加体外事件。
The abscopal effect following ionizing radiation therapy (RT) is considered to be a rare event. This effect does occur more frequently when combined with other therapies, including immunotherapy. Here we demonstrate that the frequency of abscopal events following RT alone is highly dependent upon the degree of adrenergic stress in the tumor-bearing host. Using a combination of physiologic, pharmacologic and genetic strategies, we observe improvements in the control of both irradiated and non-irradiated distant tumors, including metastatic tumors, when adrenergic stress or signaling through beta-adrenergic receptor is reduced. Further, we observe cellular and molecular evidence of improved, antigen-specific, anti-tumor immune responses which also depend upon T cell egress from draining lymph nodes. These data suggest that blockade of beta 2 adrenergic stress signaling could be a useful, safe, and feasible strategy to improve efficacy in cancer patients undergoing radiation therapy. Abscopal responses in patients and preclinical models following radiation therapy are rare. Here the authors show that, in murine tumor models, reducing adrenergic stress or beta 2-adrenergic receptor signalling not only improves control of the irradiated tumor but significantly increases abscopal events.