The Δ133p53β isoform promotes an immunosuppressive environment leading to aggressive prostate cancer
The Δ133p53β isoform promotes an immunosuppressive environment leading to aggressive prostate cancer
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DOI：
10.1038/s41419-019-1861-1
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发表时间：
2019-08-20
影响因子：
9
通讯作者：
Braithwaite, Antony W.
中科院分区：
文献类型：
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作者：
Kazantseva, Marina;Mehta, Sunali;Braithwaite, Antony W.
前列腺癌是男性第二常见的癌症，目前还没有可靠的生物标志物或靶向治疗方法。在这里，我们证明了Delta 133TP53β亚型水平的升高是前列腺癌免疫细胞(特别是T细胞和CD163+巨噬细胞)浸润的特征。这些癌症的无进展生存期较短，格里森评分为7，免疫抑制环境由较高比例的PD-1、PD-L1和集落刺激因子1受体(CSF1R)阳性细胞定义。与此一致的是，肿瘤的RNA-SEQ显示与免疫信号和细胞迁移相关的途径丰富。我们进一步证明了缺氧和野生型p53在上调Delta 133TP53水平中的作用。最后，AUC分析表明，Delta 133TP53β表达水平单独预测侵袭性疾病的准确率为88%。我们的数据证实Delta 133TP53β是侵袭性前列腺癌的一个高度准确的预后因素。
Prostate cancer is the second most common cancer in men, for which there are no reliable biomarkers or targeted therapies. Here we demonstrate that elevated levels of Delta 133TP53 beta isoform characterize prostate cancers with immune cell infiltration, particularly T cells and CD163+ macrophages. These cancers are associated with shorter progression-free survival, Gleason scores >= 7, and an immunosuppressive environment defined by a higher proportion of PD-1, PD-L1 and colony-stimulating factor 1 receptor (CSF1R) positive cells. Consistent with this, RNA-seq of tumours showed enrichment for pathways associated with immune signalling and cell migration. We further show a role for hypoxia and wild-type p53 in upregulating Delta 133TP53 levels. Finally, AUC analysis showed that Delta 133TP53 beta expression level alone predicted aggressive disease with 88% accuracy. Our data identify Delta 133TP53 beta as a highly accurate prognostic factor for aggressive prostate cancer.