An organoid-based screen for epigenetic inhibitors that stimulate antigen presentation and potentiate T-cell-mediated cytotoxicity.
An organoid-based screen for epigenetic inhibitors that stimulate antigen presentation and potentiate T-cell-mediated cytotoxicity.
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基于器官的表观遗传学抑制剂，刺激抗原表现并增强T细胞介导的细胞毒性。
DOI：
10.1038/s41551-021-00805-x
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发表时间：
2021-11
影响因子：
28.1
通讯作者：
Lu X
中科院分区：
文献类型：
--
作者：
Zhou Z;Van der Jeught K;Fang Y;Yu T;Li Y;Ao Z;Liu S;Zhang L;Yang Y;Eyvani H;Cox ML;Wang X;He X;Ji G;Schneider BP;Guo F;Wan J;Zhang X;Lu X
在乳腺癌中，遗传异质性、缺乏可操作的靶点和免疫逃避都导致免疫检查点阻断治疗的临床应答率有限。在这里，我们报告了一种基于小鼠或患者来源的乳腺肿瘤类器官和肿瘤特异性细胞毒性T细胞的功能相互作用的高通量筛选，用于鉴定促进抗原呈递和增强T细胞介导的细胞毒性的表观遗传抑制剂。我们表明，通过筛选鉴定的表观遗传抑制剂GSK-LSD 1，CUDC-101和BML-210在小鼠原位乳腺肿瘤中显示出抗肿瘤活性，它们上调了乳腺肿瘤细胞上主要组织相容性复合物I类介导的抗原呈递，并且用BML-210治疗实质上使乳腺肿瘤对检查点抑制剂程序性死亡-1敏感。通过肿瘤类器官T细胞筛选促进的肿瘤细胞杀伤活性的标准化测量可以帮助识别一系列癌症的候选免疫治疗剂。
In breast cancer, genetic heterogeneity, the lack of actionable targets, and immune evasion all contribute to the limited clinical response rates to immune checkpoint blockade therapy. Here, we report a high-throughput screen based on the functional interaction of mouse or patient-derived breast tumour organoids and tumour-specific cytotoxic T cells for the identification of epigenetic inhibitors that promote antigen presentation and that potentiate T-cell-mediated cytotoxicity. We show that the epigenetic inhibitors GSK-LSD1, CUDC-101 and BML-210, identified by the screen, display antitumour activities in orthotopic mammary tumours in mice, that they upregulate antigen presentation mediated by the major histocompatibility complex class I on breast tumour cells, and that treatment with BML-210 substantially sensitized breast tumours to the checkpoint inhibitor programmed-death-1. Standardized measurements of tumour-cell killing activity facilitated by tumour-organoid–T cell screens may aid the identification of candidate immunotherapeutics for a range of cancers.
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影响因子：
50.3
作者：
Dravis C;Chung CY;Lytle NK;Herrera-Valdez J;Luna G;Trejo CL;Reya T;Wahl GM
通讯作者：
Wahl GM
影响因子：
5.8
作者：
Gu, Zuguang;Eils, Roland;Schlesner, Matthias
通讯作者：
Schlesner, Matthias
影响因子：
14.8
作者：
Cattaneo CM;Dijkstra KK;Fanchi LF;Kelderman S;Kaing S;van Rooij N;van den Brink S;Schumacher TN;Voest EE
通讯作者：
Voest EE
DOI：
10.1186/s13058-016-0708-2
发表时间：
2016-05-11
期刊：
Breast cancer research : BCR
影响因子：
--
作者：
Gray MJ;Gong J;Hatch MM;Nguyen V;Hughes CC;Hutchins JT;Freimark BD
通讯作者：
Freimark BD
影响因子：
29.7
作者：
Blum JS;Wearsch PA;Cresswell P
通讯作者：
Cresswell P