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首页> 外文期刊>The FEBS journal >Targeting DNA damage response pathways to activate the STING innate immune signaling pathway in human cancer cells
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Targeting DNA damage response pathways to activate the STING innate immune signaling pathway in human cancer cells

机译：靶向DNA损伤响应途径以激活人癌细胞中的刺痛先天免疫信号通路

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Activating stimulator of interferon genes to turn immunologically refractive cold tumor hot is an exciting therapeutic approach to increase the clinical responsiveness of some human cancers to immune checkpoint inhibitors. DNA damaging drugs and PARP inhibitors are two types of agents that have demonstrated this potential. Inhibitors of Chk1 or Wee1 induce DNA damage in cancer cells in predominantly the S-phase population. Increased cytoplasmic single-stranded and double-stranded DNA (dsDNA) from this DNA damage resulted in increased tank-binding kinase 1 (TBK1) phosphorylation in a range of cancer cell lines. However, despite robust increases in pTBK1, no downstream consequences of TBK1 phosphorylation were observed (namely no increase in pIRF3/7, interferon regulatory factor (IRF)-dependent gene expression or a type I IFN response). In combination with cytotoxic chemotherapy such as gemcitabine or camptothecin (CPT), Chk1 inhibition increased cytoplasmic dsDNA compared with the cytotoxic alone but attenuated the cytotoxic chemotherapy-induced increase in IRF1 protein and STAT1 phosphorylation through inhibition of nuclear RelB translocation. Despite increased cytoplasmic DNA and TBK1 activation, inhibition of Chk1, ataxia telangiectasia and Rad3-related protein, or Wee1 failed to activate a type I IFN response. We discuss the potential underlying mechanisms for this lack of IRF-dependent gene response and how this might influence the clinical strategies of combining Chk1 or Wee1 inhibitors with immune checkpoint inhibitors.
机译：激活干扰素基因刺激因子使免疫屈光性冷肿瘤变热是一种令人兴奋的治疗方法，可以提高某些人类癌症对免疫检查点抑制剂的临床反应性。DNA损伤药物和PARP抑制剂是两种已经证明了这种潜力的药物。Chk1或Wee1抑制剂主要在S期人群中诱导癌细胞DNA损伤。这种DNA损伤导致的细胞质单链和双链DNA（dsDNA）增加导致一系列癌细胞系中的坦克结合激酶1（TBK1）磷酸化增加。然而，尽管pTBK1显著增加，但未观察到TBK1磷酸化的下游后果（即pIRF3/7、干扰素调节因子（IRF）依赖性基因表达或I型干扰素反应没有增加）。与单用细胞毒性化疗相比，与吉西他滨或喜树碱（CPT）等细胞毒性化疗联合使用时，Chk1抑制增加了细胞质dsDNA，但通过抑制核RelB易位减弱了细胞毒性化疗诱导的IRF1蛋白和STAT1磷酸化增加。尽管细胞质DNA和TBK1激活增加，但Chk1、共济失调毛细血管扩张和Rad3相关蛋白或Wee1的抑制未能激活I型IFN反应。我们讨论了这种缺乏IRF依赖性基因反应的潜在机制，以及这可能如何影响Chk1或Wee1抑制剂与免疫检查点抑制剂结合的临床策略。

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