Xue Junli, Chen Chunhua, Qi Manlong, Huang Yan, Wang Lin, Gao Yong, Dong Haidong, Ling Kun
Department of Oncology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai 200120, China.
Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, MN 55902, USA.
Oncotarget. 2017 Jun 27;8(26):42414-42427. doi: 10.18632/oncotarget.17123.
The programmed death-ligand 1 (PD-L1), by binding to PD-1 on the surface of immune cells, activates a major immune checkpoint pathway. Elevated expression of PD-L1 in tumor cells mediates tumor-induced T-cell exhaustion and immune suppression; therefore protect the survival of tumor cells. Although blockade of the PD-1/PD-L1 axis exhibits great potential in cancer treatment, mechanisms driving the up-regulation of PD-L1 in tumor cells remain not fully understood. Here we found that type Iγ phosphatidylinositol 4-phosphate (PtdIns(4)P) 5-kinase (PIPKIγ) is required for PD-L1 expression in triple negative breast cancer cells. Depletion of PIPKIγ inhibits both intrinsic and induced PD-L1 expression. Results from further analyses suggest that PIPKIγ promotes the transcription of the PD-L1 gene by activating the NF-κB pathway in these cells. These results demonstrate that PIPKIγ-dependent expression of PD-L1 is likely important for the progression of triple negative breast cancer.
程序性死亡配体1（PD-L1）通过与免疫细胞表面的PD-1结合，激活主要的免疫检查点通路。肿瘤细胞中PD-L1表达升高介导肿瘤诱导的T细胞耗竭和免疫抑制，从而保护肿瘤细胞的存活。尽管阻断PD-1/PD-L1轴在癌症治疗中显示出巨大潜力，但驱动肿瘤细胞中PD-L1上调的机制仍未完全了解。在此，我们发现Iγ型磷脂酰肌醇4-磷酸（PtdIns(4)P）5-激酶（PIPKIγ）是三阴性乳腺癌细胞中PD-L1表达所必需的。PIPKIγ的缺失抑制了内源性和诱导性PD-L1的表达。进一步分析结果表明，PIPKIγ通过激活这些细胞中的NF-κB途径促进PD-L1基因的转录。这些结果表明，PD-L1的PIPKIγ依赖性表达可能对三阴性乳腺癌的进展很重要。
