ADAR1缺失能够克服免疫检查点抑制剂的治疗抵抗

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近年来关于免疫治疗的研究大多围绕如何增强免疫治疗疗效，因为目前多数癌症患者对免疫检查点抑制剂的治疗不应答，而有些患者治疗后有应答但后期却产生抵抗。研究表明抑制疗效的抵抗主要是由于机体的突变损伤了抗原递呈过程。日前，美国哈佛大学的丹娜法伯癌症研究院的科研人员研究发现RNA编辑酶ADAR1能够克服免疫检查点抑制剂的治疗抵抗。ADAR1的缺失能够引起IFN的上调，同时IFN诱导的双链RNA被编辑减少，导致下游的PKR和MDA5敏感，使用PD-1检查点抑制剂治疗发现，体内CD4+、CD8+等免疫细胞数目增多、浸润增强和肿瘤细胞的生长受到了极大的抑制。同时，此作用机理绕过之前免疫治疗需经CD8+T细胞识别肿瘤细胞的途径，因此克服了机体PD-1免疫检查点抑制剂的治疗抵抗。

Loss of ADAR1 in tumours overcomes resistance to immune checkpoint blockade

图片来源：文献原文

Despite the remarkable clinical successes of immune checkpoint blockade, most patients do not respond to immunotherapy, or develop therapeutic resistance because of mutations in the interferon-γ (IFNγ)- sensing pathway or in the antigen-presentation pathway1–4. There are currently no therapeutic options to overcome acquired resistance to checkpoint blockade. We recently conducted a pooled in vivo CRISPR screen to identify genes expressed by the B16 transplantable melanoma model that, when deleted, confer sensitivity to immunotherapy. This screen identified a number of genes with the potential to modify the response to endogenous RNA species, including Adar1, which encodes an adenosine deaminase that binds to and limits the sensing of endogenous double-stranded RNA (dsRNA)6–9. Here we show that ADAR1 functions as a checkpoint that limits anti-tumour immunity by preventing the sensing of endogenous dsRNA. Loss of function of ADAR1 improves responses to PD-1 blockade and overcomes common mechanisms of resistance to immunotherapy.

ADAR1缺失能够克服免疫检查点抑制剂的治疗抵抗

尽管免疫治疗取得了可观的临床获益，但由于IFN-γ信号途径或者抗原递呈途径的相关基因突变，大多数病人还是对免疫治疗不应答或者抵抗，目前没有明确的治疗手段能够去克服免疫检查点抑制剂的抵抗。我们最近通过一个在体的CRISPR项目筛选和鉴别B16黑色素瘤肿瘤模型中的关键基因，当这些基因被删除时，机体仍能够对免疫治疗敏感。这个筛选鉴定了许多有潜能修饰内源性RNA酶的基因，包括ADAR1。ADAR1编码一种腺苷脱氨酶，能够与内源性双链RNA结合并限制其识别。本文研究发现，ADAR1作为一个检查点，能够通过阻止内源性双链RNA的识别进而限制抗肿瘤活性，而ADAR1功能的缺失增强了机体对PD-1阻断剂的应答，克服了免疫治疗的抵抗。

文献来源

Ishizuka, J. J., et al. (2018). Loss of ADAR1 in tumours overcomes resistance to immune checkpoint blockade. Nature. Doi:10.1038/s41586-018-0768-9

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