Targeted Therapy Team, The Institute of Cancer Research, London, UK.
Translational Immunotherapy Team, The Institute of Cancer Research, London, UK.
Nat Rev Cancer. 2020 Apr;20(4):203-217. doi: 10.1038/s41568-020-0246-1. Epub 2020 Mar 11.
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.
免疫检查点抑制剂（ICIs）的发展正在彻底改变我们对癌症治疗的看法。即便如此，对于大多数类型的癌症，目前只有少数患者受益于 ICI 治疗。ICI 治疗的内在和获得性耐药促使研究转向新的联合治疗方法，旨在提高反应率、缓解深度和获益持久性。在这篇综述中，我们描述了放射疗法如何通过其免疫调节作用成为与 ICI 联合治疗的有前途的伙伴。我们描述了最近关于放射疗法联合 DNA 损伤反应（DDR）抑制剂的研究如何用于增强这种方法。放射疗法可以杀死癌细胞，同时触发促炎介质的释放并增加肿瘤浸润免疫细胞 - 这种现象通常被通俗地描述为使免疫上“冷”的肿瘤“热”起来。在这里，我们重点介绍新的发展，这些发展说明了放射疗法后肿瘤细胞自主信号的关键作用。放射诱导的肿瘤细胞微核激活细胞质核酸传感器途径，如环鸟苷酸-腺苷酸合酶 (cGAS)-干扰素基因刺激物 (STING)，并传播由此产生的炎症信号重塑了肿瘤微环境的免疫结构。平行地，辐射可以通过调节新抗原表达来影响免疫监视。最后，我们强调了如何通过结合 DDR 抑制剂、ICI 和放射疗法来利用肿瘤细胞自主机制。
