PDF(Pubmed)
Abstract：
A high level of PD-L1 in cancer cells promotes tumor immune escape and inhibits tumor immunotherapy. Although PD-L1 gene expression is upregulated by multiple pathways, its gene transcriptional repression is still unclear. Here we found that loss of PPARα, one of the peroxisome-proliferator-activated receptors (PPARs) family members, promoted colorectal tumor immune escape. Mechanistically, PPARα directly bound to the PD-L1 promoter resulting in its gene transcriptional repression, which in turn increased T cell activity, and PPARα agonist enhanced this event. However, ERK induced PPARα-S12 phosphorylation leading to blockade of PPARα-mediated PD-L1 transcriptional repression, and the combination of ERK inhibitor with PPARα agonist significantly inhibited tumor immune escape. These findings suggest that the ERK-PPARα pathway inhibited PD-L1 gene transcriptional repression and promoted colorectal tumor immune escape.
摘要：
癌细胞上高水平的PD-L1促进肿瘤免疫逃逸并抑制肿瘤免疫治疗。尽管PD-L1基因表达通过多种途径上调,其基因转录抑制仍不清楚。在这里我们发现PPARα的损失，过氧化物酶体增殖物激活受体（PPARs）家族成员之一，促进结直肠肿瘤免疫逃逸。机械上,PPARα直接与PD-L1启动子结合，导致其基因转录抑制，这反过来又增加了T细胞的活性，PPARα激动剂增强了这一事件。然而,ERK诱导PPARα-S12磷酸化导致阻断PPARα介导的PD-L1转录抑制,ERK抑制剂与PPARα激动剂的组合显着抑制了肿瘤的免疫逃逸。提示ERK-PPARα通路抑制PD-L1基因转录抑制，促进结直肠肿瘤免疫逃逸。
