Department of Medicine, Division of Hematology and Oncology, University of California, Los Angeles, Los Angeles, CA, USA.
Department of Molecular and Medical Pharmacology, University of California, Los Angeles, Los Angeles, CA, USA.
Nat Cancer. 2020;1(1):46-58. doi: 10.1038/s43018-019-0003-0. Epub 2019 Dec 9.
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 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 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.
免疫细胞浸润肿瘤不足是癌症患者对程序性细胞死亡蛋白 1 (PD-1) 阻断疗法产生原发性耐药的主要机制。有人推测，癌细胞内在机制可能主动将 T 细胞排除在肿瘤之外，这表明发现可作用于抑制以增加 T 细胞浸润的活性分子可能与检查点抑制剂免疫疗法协同作用。在这里，我们发现 p21 激活激酶 4 (PAK4) 在 T 细胞和树突状细胞浸润低的无应答肿瘤活检中富集。在小鼠模型中，PAK4 的基因缺失增加了 T 细胞浸润，并以 CD8 T 细胞依赖的方式逆转了对 PD-1 阻断的耐药性。此外，与单独使用抗 PD-1 相比，抗 PD-1 与 PAK4 抑制剂 KPT-9274 的联合使用改善了抗肿瘤反应。因此，高表达与 T 细胞和树突状细胞浸润低以及对 PD-1 阻断无反应相关，可通过抑制 PAK4 逆转。
