Targeting the Innate Immune Kinase IRAK1 in Radioresistant Cancer: Double-Edged Sword or One-Two Punch?
Targeting the Innate Immune Kinase IRAK1 in Radioresistant Cancer: Double-Edged Sword or One-Two Punch?
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DOI：
10.3389/fonc.2019.01174
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发表时间：
2019-11-13
影响因子：
4.7
通讯作者：
Sidi, Samuel
中科院分区：
文献类型：
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作者：
Liu, Peter H.;Sidi, Samuel
抗肿瘤免疫已经成为放射治疗（RT）的有利副产品，由此从辐射细胞释放的肿瘤相关抗原对位于辐射场内外的肿瘤释放先天性和适应性攻击。RT诱导的免疫反应进一步提供了克服肿瘤对RT（R-RT）耐药性的可操作靶点;使用检查点抑制剂或Toll样受体（TLR）激动剂的免疫治疗（IT）可以显着改善（如果不是协同作用）临床前模型中的RT，并且目前正在研究这些药物中的几种作为患者的放射增敏剂。在肿瘤R-RT的斑马鱼模型中的无偏化学遗传筛选中，我们意外地发现白细胞介素1受体相关激酶1（IRAK 1），TLR介导的先天免疫的核心效应子，也在活鱼和人类癌症模型中起作用，以对抗由PIDDosome复合物（PIDD-RAIDD-caspase-2）介导的RT诱导的细胞死亡。IRAK 1既作为内在肿瘤R-RT的驱动因子，又作为RT诱导的抗肿瘤免疫的效应子，乍一看，这会带来明显的治疗难题。预期IRAK 1抑制剂将使经照射的肿瘤对RT敏感，但同时阻碍由基质树突细胞引发的RT诱导的抗肿瘤免疫。相反，基于TLR激动剂的免疫疗法有望增强RT诱导的抗肿瘤免疫力，但代价是在照射的肿瘤中促进IRAK 1介导的细胞存活。我们讨论了IRAK 1在辐射与TLR反应中对催化活性的差异依赖如何有助于克服这些障碍，以及开发缺乏IRAK 4活性的IRAK 1抑制剂的至关重要性，IRAK 4的激酶活性对IRAK 1在两种途径中的激活至关重要。
Antitumor immunity has emerged as a favorable byproduct of radiation therapy (RT), whereby tumor-associated antigens released from irradiated cells unleash innate and adaptive attacks on tumors located both within and outside the radiation field. RT-induced immune responses further provide actionable targets for overcoming tumor resistance to RT (R-RT); immunotherapy (IT) with checkpoint inhibitors or Toll-like receptor (TLR) agonists can markedly improve, if not synergize with, RT in preclinical models, and several of these drugs are currently investigated as radiosensitizers in patients. In an unbiased chemical-genetic screen in a zebrafish model of tumor R-RT, we unexpectedly found that Interleukin 1 Receptor-Associated Kinase 1 (IRAK1), a core effector of TLR-mediated innate immunity, also functions in live fish and human cancer models to counter RT-induced cell death mediated by the PIDDosome complex (PIDD-RAIDD-caspase-2). IRAK1 acting both as a driver of intrinsic tumor R-RT and as an effector of RT-induced antitumor immunity would, at first glance, pose obvious therapeutic conundrums. IRAK1 inhibitors would be expected to sensitize the irradiated tumor to RT but simultaneously thwart RT-induced antitumor immunity as initiated by stromal dendritic cells. Conversely, TLR agonist-based immunotherapy would be expected to intensify RT-induced antitumor immunity but at the expense of fueling IRAK1-mediated cell survival in the irradiated tumor. We discuss how IRAK1's differential reliance on catalytic activity in the radiation vs. TLR responses might help overcome these hurdles, as well as the crucial importance of developing IRAK1 inhibitors that lack activity against IRAK4, the kinase activity of which is essential for IRAK1 activation in both pathways.