TY - JOUR
T1 - PAK4 inhibition improves PD-1 blockade immunotherapy
AU - Abril-Rodriguez, Gabriel
AU - Torrejon, Davis Y.
AU - Liu, Wei
AU - Zaretsky, Jesse M.
AU - Nowicki, Theodore S.
AU - Tsoi, Jennifer
AU - Puig-Saus, Cristina
AU - Baselga-Carretero, Ignacio
AU - Medina, Egmidio
AU - Quist, Michael J.
AU - Garcia, Alejandro J.
AU - Senapedis, William
AU - Baloglu, Erkan
AU - Kalbasi, Anusha
AU - Cheung-Lau, Gardenia
AU - Berent-Maoz, Beata
AU - Comin-Anduix, Begoña
AU - Hu-Lieskovan, Siwen
AU - Wang, Cun Yu
AU - Grasso, Catherine S.
AU - Ribas, Antoni
N1 - Publisher Copyright:
© 2019, The Author(s), under exclusive licence to Springer Nature Limited.
PY - 2020/1/1
Y1 - 2020/1/1
N2 - 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.
AB - 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.
UR - https://www.scopus.com/pages/publications/85085377197
U2 - 10.1038/s43018-019-0003-0
DO - 10.1038/s43018-019-0003-0
M3 - Article
C2 - 34368780
AN - SCOPUS:85085377197
SN - 2662-1347
VL - 1
SP - 46
EP - 58
JO - Nature Cancer
JF - Nature Cancer
IS - 1
ER -