Inhibition of PAK1 suppresses pancreatic cancer by stimulation of anti-tumour immunity through down-regulation of PD-L1.

2020-03-01

Wang, Kai

Zhan, Yifan

Huynh, Nhi

Dumesny, Chelsea

Wang, Xiao

Asadi, Khashayer

Herrmann, David

Timpson, Paul

Yang, Yang

Walsh, Katrina

Baldwin, Graham S

Nikfarjam, Mehrdad

He, Hong

Pancreatic stellate cells

Programmed death-ligand 1

Tumour microenvironment

p21-activated kinase 1

Journal Article

0000-0003-4866-276X

0000-0002-0944-8747

10.1016/j.canlet.2019.12.020

Immunotherapies have not yielded significant clinical benefits for pancreatic ductal adenocarcinoma (PDA) because of the existence of an immunosuppressive tumour microenvironment (TME) characterized by a desmoplastic stroma containing infiltrated immune cells and activated pancreatic stellate cells (PSCs). This study aims to investigate the involvement of PAK1 in anti-tumour immunity. In PDA patients, low PAK1 expression, low activation of PSC and high CD8+ T cell/PAK1 ratios correlated with longer overall survival. In a murine PDA model, PAK1 knockout increased intra-tumoral CD4+ and CD8+ T cells, inhibited PSCs activation and extended survival. Inhibition of PAK1 reduced PSC-stimulated PDA cell proliferation and migration, blocked PSC-mediated protection of PDA cells from killing by cytotoxic lymphocytes and decreased intrinsic and PSC-stimulated PD-L1 expression in PDA cells, which further sensitized PDA cells to cytotoxic lymphocytes. Inhibition of PAK1 stimulates anti-tumour immunity by increasing intra-tumoral CD4+ and CD8+ T cells, and by sensitizing PDA cells to killing by cytotoxic lymphocytes via down-regulation of intrinsic and PSC-stimulated PD-L1 expression. PAK1 inhibitors, especially in combination with immune checkpoint inhibitors may result in improved efficacy of immunotherapy of PDA.

link

Cancer letters 2019; 472: 8-18

Cancer letters