Loss of ADAR1 in tumours overcomes resistance to immune checkpoint blockade
Loss of ADAR1 in tumours overcomes resistance to immune checkpoint blockade
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DOI：
10.1038/s41586-018-0768-9
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发表时间：
2019-01-03
期刊：
影响因子：
64.8
通讯作者：
Haining, W. Nicholas
中科院分区：
文献类型：
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作者：
Ishizuka, Jeffrey J.;Manguso, Robert T.;Haining, W. Nicholas
大多数癌症患者要么对免疫检查点阻断没有反应，要么对其产生耐药性，这通常是因为获得性突变损害了抗原呈递。在这里，我们表明，肿瘤细胞中RNA编辑酶ADAR 1功能的丧失使肿瘤对免疫疗法更加敏感，并克服了对检查点阻断的抵抗力。在缺乏ADAR 1的情况下，干扰素诱导的RNA种类的A至I编辑减少，导致PKR和MDA 5的双链RNA配体感测;这分别导致生长抑制和肿瘤炎症。ADAR 1的缺失克服了由肿瘤细胞抗原呈递失活引起的对PD-1检查点阻断的抗性。因此，有效的抗肿瘤免疫受到抑制性检查点如ADAR 1的限制，其限制了先天配体的感知。在对干扰素敏感的肿瘤中诱导足够的炎症可以绕过对CD 8（+）T细胞识别癌细胞的治疗要求，并且可以提供克服免疫疗法抗性的一般策略。
Most patients with cancer either do not respond to immune checkpoint blockade or develop resistance to it, often because of acquired mutations that impair antigen presentation. Here we show that loss of function of the RNA-editing enzyme ADAR1 in tumour cells profoundly sensitizes tumours to immunotherapy and overcomes resistance to checkpoint blockade. In the absence of ADAR1, A-to-I editing of interferon-inducible RNA species is reduced, leading to double-stranded RNA ligand sensing by PKR and MDA5; this results in growth inhibition and tumour inflammation, respectively. Loss of ADAR1 overcomes resistance to PD-1 checkpoint blockade caused by inactivation of antigen presentation by tumour cells. Thus, effective anti-tumour immunity is constrained by inhibitory checkpoints such as ADAR1 that limit the sensing of innate ligands. The induction of sufficient inflammation in tumours that are sensitized to interferon can bypass the therapeutic requirement for CD8(+) T cell recognition of cancer cells and may provide a general strategy to overcome immunotherapy resistance.