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PAK4抑制可改善PD-1阻断免疫治疗

原文发布日期：2019-12-09

英文摘要：

摘要翻译：

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文章：

PAK4抑制可改善PD-1阻断免疫治疗

PAK4 inhibition improves PD-1 blockade immunotherapy

原文发布日期：2019-12-09

英文摘要：

Lack of tumor infiltration by immune cells is the main mechanism of primary resistance to programmed cell death protein 1 (PD-1) blockade therapies for cancer. It has been postulated that cancer cell-intrinsic mechanisms may actively exclude T cells from tumors, suggesting that the finding of actionable molecules that could be inhibited to increase T cell infiltration may synergize with checkpoint inhibitor immunotherapy. Here, we show that p21-activated kinase 4 (PAK4) is enriched in non-responding tumor biopsies with low T cell and dendritic cell infiltration. In mouse models, genetic deletion of PAK4 increased T cell infiltration and reversed resistance to PD-1 blockade in a CD8 T cell-dependent manner. Furthermore, combination of anti-PD-1 with the PAK4 inhibitor KPT-9274 improved anti-tumor response compared with anti-PD-1 alone. Therefore, high PAK4 expression is correlated with low T cell and dendritic cell infiltration and a lack of response to PD-1 blockade, which could be reversed with PAK4 inhibition.

摘要翻译：

免疫细胞缺乏肿瘤渗透是针对PD-1抑制疗法治疗癌症的 primary 阻抗的主要机制。研究表明，癌细胞可能通过自身机制阻止T细胞进入肿瘤，这表明能够被抑制以增强T细胞浸润的分子活性物质有望与检针免疫疗法协同发挥作用。在此，我们发现，在低T细胞和树突状细胞浸润的非应答肿瘤活检中，p21-激活激酶4（PAK4）表达高度富集。在小鼠模型中，去除非编码区的PAK4通过CD8 T细胞依赖性地增加T细胞浸润，并逆转了对PD-1阻断疗法的抗性。此外，在联合使用抗-PD-1和PAK4抑制剂KPT-9274的情况下，肿瘤反应率优于单独使用抗-PD-1治疗。因此，高PAK4表达与低T细胞和树突状细胞浸润以及PD-1阻断疗法的无应答相关，并且可以通过抑制PAK4得到恢复。