文章：

放疗后肿瘤细胞对炎症微环境的重塑

Inflammatory microenvironment remodelling by tumour cells after radiotherapy

原文发布日期：2020-03-11

DOI: 10.1038/s41568-020-0246-1

类型: Review Article

开放获取: 否

英文摘要：

The development of immune checkpoint inhibitors (ICIs) is revolutionizing the way we think about cancer treatment. Even so, for most types of cancer, only a minority of patients currently benefit from ICI therapies. Intrinsic and acquired resistance to ICIs has focused research towards new combination therapy approaches that seek to increase response rates, the depth of remission and the durability of benefit. In this Review, we describe how radiotherapy, through its immunomodulating effects, represents a promising combination partner with ICIs. We describe how recent research on DNA damage response (DDR) inhibitors in combination with radiotherapy may be used to augment this approach. Radiotherapy can kill cancer cells while simultaneously triggering the release of pro-inflammatory mediators and increasing tumour-infiltrating immune cells – phenomena often described colloquially as turning immunologically ‘cold’ tumours ‘hot’. Here, we focus on new developments illustrating the key role of tumour cell-autonomous signalling after radiotherapy. Radiotherapy-induced tumour cell micronuclei activate cytosolic nucleic acid sensor pathways, such as cyclic GMP–AMP synthase (cGAS)–stimulator of interferon genes (STING), and propagation of the resulting inflammatory signals remodels the immune contexture of the tumour microenvironment. In parallel, radiation can impact immunosurveillance by modulating neoantigen expression. Finally, we highlight how tumour cell-autonomous mechanisms might be exploited by combining DDR inhibitors, ICIs and radiotherapy.

摘要翻译： 

免疫检查点抑制剂（ICI）的发展正在彻底改变我们对癌症治疗的认知。然而，就大多数癌症类型而言，目前仅有少数患者能从ICI疗法中获益。对ICI的固有及获得性耐药问题促使研究转向新的联合疗法策略，旨在提高治疗应答率、缓解深度及疗效持久性。本文综述中，我们探讨了放疗如何通过其免疫调节效应成为与ICI联合治疗的有望组合，并阐述了近期关于DNA损伤反应（DDR）抑制剂联合放疗的研究如何增强该策略的疗效。放疗在杀死癌细胞的同时，能触发促炎介质释放并增加肿瘤浸润免疫细胞——这种现象常被通俗地描述为将免疫“冷”肿瘤转化为“热”肿瘤。我们重点分析了放疗后肿瘤细胞自主信号传导的关键作用：放疗诱导的肿瘤细胞微核激活胞质核酸传感通路（如cGAS-STING通路），其产生的炎症信号传导重塑了肿瘤微环境的免疫格局。同时，放疗可通过调节新抗原表达影响免疫监视。最后，我们强调了如何通过联合使用DDR抑制剂、ICI和放疗来利用肿瘤细胞自主机制。

原文链接：

Inflammatory microenvironment remodelling by tumour cells after radiotherapy