In vivo CRISPR screening identifies Ptpn2 as a cancer immunotherapy target.
In vivo CRISPR screening identifies Ptpn2 as a cancer immunotherapy target.
复制标题
DOI：
10.1038/nature23270
复制
发表时间：
2017-07-27
期刊：
影响因子：
64.8
通讯作者：
Haining WN
中科院分区：
文献类型：
--
作者：
Manguso RT;Pope HW;Zimmer MD;Brown FD;Yates KB;Miller BC;Collins NB;Bi K;LaFleur MW;Juneja VR;Weiss SA;Lo J;Fisher DE;Miao D;Van Allen E;Root DE;Sharpe AH;Doench JG;Haining WN
PD-1检查点阻断的免疫治疗仅在少数癌症患者中有效，这表明需要额外的治疗策略。在这里，我们使用了一种合并的体内遗传筛选方法，在接受免疫治疗的小鼠的可移植肿瘤中使用CRISPR-Cas9基因组编辑来发现以前未描述的免疫治疗靶点。我们测试了黑色素瘤细胞表达的2，368个基因，以确定那些与检查点封锁协同作用或导致抵抗的基因。我们回收了已知的免疫逃避分子PD-L1和CD 47，并证实了干扰素-γ信号传导的缺陷导致了对免疫疗法的抵抗。通过删除参与几种不同途径的基因，包括NF-κB信号传导、抗原呈递和未折叠蛋白应答，使肿瘤对免疫疗法敏感。此外，肿瘤细胞中蛋白酪氨酸磷酸酶PTPN 2的缺失通过增强干扰素-γ介导的对抗原呈递和生长抑制的作用来增加免疫疗法的功效。肿瘤模型中的体内遗传筛选可以在未预料到的途径中识别新的免疫治疗靶点。
Immunotherapy with PD-1 checkpoint blockade is effective in only a minority of patients with cancer, suggesting that additional treatment strategies are needed. Here we use a pooled in vivo genetic screening approach using CRISPR–Cas9 genome editing in transplantable tumours in mice treated with immunotherapy to discover previously undescribed immunotherapy targets. We tested 2,368 genes expressed by melanoma cells to identify those that synergize with or cause resistance to checkpoint blockade. We recovered the known immune evasion molecules PD–L1 and CD47, and confirmed that defects in interferon-γ signalling caused resistance to immunotherapy. Tumours were sensitized to immunotherapy by deletion of genes involved in several diverse pathways, including NF-κB signalling, antigen presentation and the unfolded protein response. In addition, deletion of the protein tyrosine phosphatase PTPN2 in tumour cells increased the efficacy of immunotherapy by enhancing interferon-γ-mediated effects on antigen presentation and growth suppression. In vivo genetic screens in tumour models can identify new immunotherapy targets in unanticipated pathways.
登录
查看更多内容
影响因子：
30.8
作者：
通讯作者：
--
影响因子：
7.3
作者：
Morandi F;Pistoia V
通讯作者：
Pistoia V
影响因子：
64.8
作者：
Ebert, Benjamin L.;Pretz, Jennifer;Bosco, Jocelyn;Chang, Cindy Y.;Tamayo, Pablo;Galili, Naomi;Raza, Azra;Root, David E.;Attar, Eyal;Ellis, Steven R.;Golub, Todd R.
通讯作者：
Golub, Todd R.
CRISPR-CAS9介导的基因失活的高度活性SGRNA的合理设计。
影响因子：
46.9
作者：
Doench, John G.;Hartenian, Ella;Graham, Daniel B.;Tothova, Zuzana;Hegde, Mudra;Smith, Ian;Sullender, Meagan;Ebert, Benjamin L.;Xavier, Ramnik J.;Root, David E.
通讯作者：
Root, David E.
影响因子：
2.1
作者：
Olshen, AB;Venkatraman, ES;Wigler, M
通讯作者：
Wigler, M