In vivo multidimensional CRISPR screens identify Lgals2 as an immunotherapy target in triple-negative breast cancer.
In vivo multidimensional CRISPR screens identify Lgals2 as an immunotherapy target in triple-negative breast cancer.
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体内多维 CRISPR 筛选将 Lgals2 鉴定为三阴性乳腺癌的免疫治疗靶点
DOI：
10.1126/sciadv.abl8247
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发表时间：
2022-07
期刊：
影响因子：
13.6
通讯作者：
中科院分区：
文献类型：
--
作者：
免疫检查点抑制剂在三阴性乳腺癌（TNBC）患者中表现出有限的应答率，这表明可能存在其他免疫逃逸机制。在这里，我们使用具有多维免疫缺陷特征的不同小鼠模型进行了两步定制的体内CRISPR筛选，靶向疾病相关的免疫基因。体内筛选表征了不同肿瘤微环境中的基因功能，并恢复了典型的免疫治疗靶点，如Ido 1。此外，功能筛选和转录组学分析将Lgals 2鉴定为涉及免疫逃逸的TNBC中的候选调节剂。机制研究表明，肿瘤细胞内源性Lgals 2诱导肿瘤相关巨噬细胞数量增加，以及通过CSF 1/CSF 1 R轴的M2样极化和巨噬细胞增殖，这导致TNBC微环境的免疫抑制性质。使用抑制性抗体阻断LGALS 2成功地阻止了肿瘤生长并逆转了免疫抑制。总的来说，我们的研究结果为LGALS 2作为TNBC的潜在免疫治疗靶点提供了理论基础。
Immune checkpoint inhibitors exhibit limited response rates in patients with triple-negative breast cancer (TNBC), suggesting that additional immune escape mechanisms may exist. Here, we performed two-step customized in vivo CRISPR screens targeting disease-related immune genes using different mouse models with multidimensional immune-deficiency characteristics. In vivo screens characterized gene functions in the different tumor microenvironments and recovered canonical immunotherapy targets such as Ido1. In addition, functional screening and transcriptomic analysis identified Lgals2 as a candidate regulator in TNBC involving immune escape. Mechanistic studies demonstrated that tumor cell–intrinsic Lgals2 induced the increased number of tumor-associated macrophages, as well as the M2-like polarization and proliferation of macrophages through the CSF1/CSF1R axis, which resulted in the immunosuppressive nature of the TNBC microenvironment. Blockade of LGALS2 using an inhibitory antibody successfully arrested tumor growth and reversed the immune suppression. Collectively, our results provide a theoretical basis for LGALS2 as a potential immunotherapy target in TNBC.
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DOI：
10.1093/bioinformatics/btu638
发表时间：
2015-01-15
期刊：
Bioinformatics (Oxford, England)
影响因子：
--
作者：
Anders S;Pyl PT;Huber W
通讯作者：
Huber W
影响因子：
8
作者：
Li H;Zhao L;Lau YS;Zhang C;Han R
通讯作者：
Han R
三阴性乳腺癌的基因组和转录组景观：亚型和治疗策略
影响因子：
50.3
作者：
Jiang, Yi-Zhou;Ma, Ding;Shao, Zhi-Ming
通讯作者：
Shao, Zhi-Ming
影响因子：
7.3
作者：
Chambers AM;Lupo KB;Matosevic S
通讯作者：
Matosevic S
影响因子：
64.5
作者：
Dong, Matthew B.;Wang, Guangchuan;Chen, Sidi
通讯作者：
Chen, Sidi