The immune checkpoint ligand PD-L1 is upregulated in EMT-activated human breast cancer cells by a mechanism involving ZEB-1 and miR-200
The immune checkpoint ligand PD-L1 is upregulated in EMT-activated human breast cancer cells by a mechanism involving ZEB-1 and miR-200
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DOI：
10.1080/2162402x.2016.1263412
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发表时间：
2017-01-01
期刊：
影响因子：
7.2
通讯作者：
Chouaib, Salem
中科院分区：
文献类型：
--
作者：
Noman, Muhammad Zaeem;Janji, Bassam;Chouaib, Salem
间充质肿瘤细胞的PD-L1表达和调控在很大程度上仍不明确。在这里，我们报告了在不同的EMT激活的MCF 7人乳腺癌细胞克隆中，PD-L1在MCF 7 sh-WISP 2、MCF 7 -1001/2101和MDA-MB-231细胞中差异性上调，但在MCF 7 SNAI 1和MCF 7 SNAI 1 -6SA细胞中不上调。机制研究表明，ZEB-1的siRNA沉默，而不是SNAI 1，TWIST，或SLUG和miR 200家族成员在MCF 7 sh-WISP 2细胞中的过表达强烈降低PD-L1表达。因此，我们认为EMT激活的乳腺癌细胞中PD-L1的表达依赖于参与EMT激活的EMT-TF。有趣的是，siRNA介导的PD-L1靶向或抗体介导的PD-L1阻断恢复了高度耐药的MCF 7 sh-WISP 2和MCF 7 -2101细胞对CTL介导的杀伤的易感性。此外，这些结果提供了一种新的临床前原理，以探索EMT抑制剂作为佐剂，以增强恶性进展由不同EMT-TF驱动的患者亚组的免疫应答。
PD-L1 expression and regulation by mesenchymal tumor cells remain largely undefined. Here, we report that among different EMT-activated MCF7 human breast cancer cell clones, PD-L1 was differentially upregulated in MCF7 sh-WISP2, MCF7-1001/2101, and MDA-MB-231 cells but not in MCF7 SNAI1 and MCF7 SNAI1-6SA cells. Mechanistic investigations revealed that siRNA silencing of ZEB-1, but not SNAI1, TWIST, or SLUG and overexpression of miR200 family members in MCF7 sh-WISP2 cells strongly decreased PD-L1 expression. Thus, we propose that PD-L1 expression in EMT-activated breast cancer cells depends on the EMT-TF involved in EMT activation. Interestingly, siRNA-mediated targeting of PD-L1 or anti-bodymediated PD-L1 block restored the susceptibility of highly resistant MCF7 sh-WISP2 and MCF7-2101 cells to CTL-mediated killing. Additionally, these results provide a novel preclinical rationale to explore EMT inhibitors as adjuvants to boost immunotherapeutic responses in subgroups of patients in whom malignant progression is driven by different EMT-TFs.