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.

免疫细胞缺乏肿瘤浸润是对癌症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。据推测，癌细胞内在机制可能会主动将 T 细胞排除在肿瘤之外，这表明发现可抑制增加 T 细胞浸润的可操作分子可能与检查点抑制剂免疫疗法产生协同作用。在这里，我们显示 p21 激活激酶 4 (PAK4) 在 T 细胞和树突细胞浸润低的无反应肿瘤活检中富集。在小鼠模型中， PAK4的基因缺失以 CD8 T 细胞依赖性方式增加 T 细胞浸润并逆转对 PD-1 阻断的抗性。此外，与单独的抗 PD-1 相比，抗 PD-1 与 PAK4 抑制剂 KPT-9274 的组合改善了抗肿瘤反应。因此，高PAK4表达与低 T 细胞和树突状细胞浸润以及对 PD-1 阻断缺乏反应相关，这可以通过 PAK4 抑制来逆转。