Drug-induced PD-L1 expression and cell stress response in breast cancer cells can be balanced by drug combination
Drug-induced PD-L1 expression and cell stress response in breast cancer cells can be balanced by drug combination
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DOI：
10.1038/s41598-019-51537-7
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发表时间：
2019-10-22
影响因子：
4.6
通讯作者：
Lonard, David M.
中科院分区：
文献类型：
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作者：
Gilad, Yosi;Eliaz, Yossi;Lonard, David M.
化疗对肿瘤-免疫系统相互作用的影响可能是有益的，也可能是有害的，其表现为免疫原性细胞死亡（ICD）范式或免疫抑制蛋白-程序性死亡配体1 （PD-L1）的过度表达。在这项研究中，我们探讨了类固醇受体共激活因子抑制剂、其他靶向抗癌化合物和传统化疗药物对四种乳腺癌细胞系PD-L1表达的影响。我们的研究结果表明，这些药物诱导PD-L1表达，但这种诱导的程度在不同的化合物之间存在很大差异。此外，我们利用E0771 ER + BC细胞作为模型，更详细地研究了药理压力、细胞应激和PD-L1诱导之间的关系。我们的研究结果表明，药物诱导的PD-L1表达发生在更广泛的细胞应激背景下，而不会产生获得性耐药。此外，BC细胞毒性、诱导细胞应激和PD-L1过表达之间的平衡可以通过选择适当的抗癌化合物组合来实现。因此，我们建议联合用药不仅可以增加对癌细胞的直接杀伤，还可以作为一种策略，在药物治疗期间最小化免疫抑制和癌细胞促生存程序反应的激活。
The impact of chemotherapy on tumor-immune system interaction can be either beneficial or harmful, which is represented by the immunogenic cell death (ICD) paradigm or overexpression of the immunosuppressive protein - programmed death ligand 1 (PD-L1). In this study we explore the impact of steroid receptor coactivator inhibitor, other targeted anti-cancer compounds and traditional chemotherapeutic agents on the expression of PD-L1 in four breast cancer (BC) cell lines. Our results show that these agents induce PD-L1 expression, yet the magnitude of this induction varies substantially across the different compounds. In addition, we utilized the E0771 ER + BC cells as a model to examine in greater detail the relationship between pharmacological pressure, cell stress and the induction of PD-L1. Our results imply that drug induced PD-L1 expression occurs in the broader context of cell-stress, without conferring acquired drug-resistance. Furthermore, a balance between BC cytotoxicity, induction of cell-stress and the overexpression of PD-L1 can be achieved through the selection of appropriate combinations of anti-cancer compounds. Therefore, we propose that drug combination can be employed not only for increasing the direct kill of cancer cells, but also as a strategy to minimize the activation of immunosuppressive and cancer cell pro-survival program responses during drug treatment.