封锁
渗透(HVAC)
免疫疗法
癌症研究
PD-L1
CD8型
癌症免疫疗法
免疫系统
细胞
T细胞
细胞毒性T细胞
化学
免疫检查点
生物
免疫学
受体
材料科学
生物化学
体外
复合材料
作者
Gabriel Abril-Rodríguez,Davis Y. Torrejon,Wei Liu,Jesse M. Zaretsky,Theodore S. Nowicki,Jennifer Tsoi,Cristina Puig-Saus,Ignacio Baselga-Carretero,Egmidio Medina,Michael J. Quist,Alejandro J. Garcia,William Senapedis,Erkan Baloglu,Anusha Kalbasi,Gardenia Cheung-Lau,Beata Berent-Maoz,Begoña Comı́n-Anduix,Siwen Hu‐Lieskovan,Cun‐Yu Wang,Catherine S. Grasso,Antoni Ribas
出处
期刊:Nature cancer
[Springer Nature]
日期:2019-12-09
卷期号:1 (1): 46-58
被引量:97
标识
DOI:10.1038/s43018-019-0003-0
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.
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