Remodeling of the Tumor Microenvironment Through PAK4 Inhibition Sensitizes Tumors to Immune Checkpoint Blockade

被引:0
作者
Abril-Rodriguez, Gabriel [1 ,2 ]
Torrejon, Davis Y. [1 ]
Karin, Daniel [1 ,2 ]
Campbell, Katie M. [1 ]
Medina, Egmidio [1 ]
Saco, Justin D. [1 ]
Galvez, Mildred [1 ]
Champhekar, Ameya S. [1 ]
Perez-Garcilazo, Ivan [1 ]
Baselga-Carretero, Ignacio [1 ]
Singh, Jas [3 ]
Comin-Anduix, Begona [4 ,5 ]
Puig-Saus, Cristina [1 ,5 ,6 ]
Ribas, Antoni [1 ,2 ,4 ,5 ,6 ,7 ]
机构
[1] Univ Calif Los Angeles UCLA, Dept Med, Div Hematol Oncol, Los Angeles, CA USA
[2] UCLA, Dept Mol & Med Pharmacol, Los Angeles, CA USA
[3] Arcus Biosci Inc, Hayward, CA USA
[4] UCLA, Dept Surg, Div Surg Oncol, Los Angeles, CA USA
[5] Jonsson Comprehens Canc Ctr, Los Angeles, CA USA
[6] Parker Inst Canc Immunotherapy, San Francisco, CA USA
[7] Univ Calif Los Angeles, Jonsson Comprehens Canc Ctr, 10833 Le Conte Ave, Los Angeles, CA 90095 USA
来源
CANCER RESEARCH COMMUNICATIONS | 2022年 / 2卷 / 10期
关键词
DENDRITIC CELLS; RESISTANCE; CANCER; IMMUNOTHERAPY; ACTIVATION; TRAFFICKING; PROGNOSIS; PATHWAYS; SURVIVAL; RECEPTOR;
D O I
10.1158/2767-9764.CRC-21-0133
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
PAK4 inhibition can sensitize tumors to immune checkpoint blockade (ICB) therapy; however, the underlying mechanisms remain unclear. We re-port that PAK4 inhibition reverses immune cell exclusion by increasing the infiltration of CD8 T cells and CD103+ dendritic cells (DC), a specific type of DCs that excel at cross-presenting tumor antigens and constitute a source of CXCL10. Interestingly, in melanoma clinical datasets, PAK4 expression levels negatively correlate with the presence of CCL21 , the ligand for CCR7 expressed in CD103+ DCs. Furthermore, we extensively characterized the transcriptome of PAK4 knockout (KO) tumors, in vitro and in vivo , and established the importance of PAK4 expression in the regulation of the extracellular matrix, which can facilitate immune cell infiltration. Compar-ison between PAK4 wild type and KO anti-PD-1 treated tumors revealed how PAK4 deletion sensitizes tumors to ICB from a transcriptomic per-spective. In addition, we validated genetically and pharmacologically that inhibition of PAK4 kinase activity is sufficient to improve antitumor efficacy of anti-PD-1 blockade in multiple melanoma mouse models. Therefore, this study provides novel insights into the mechanism of action of PAK4 inhi-bition and provides the foundation for a new treatment strategy that aims to overcome resistance to PD-1 blockade by combining anti-PD-1 with a small-molecule PAK4 kinase inhibitor.Significance: Our findings provide new insights into PAK4 inhibition mechanism of action as well as the scientific foundation for specifically blocking PAK4 kinase activity using a novel and specific PAK4 kinase inhibitor to overcome resistance to PD-1 blockade.
引用
收藏
页码:1214 / 1228
页数:15
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