Inhibition of PAK1 suppresses pancreatic cancer by stimulation of anti-tumour immunity through down-regulation of PD-L1. (1st March 2020)

• Record Type: Journal Article
• Authors: 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
• Is Part Of: Cancer letters. Volume 472(2020)
• Page Start: 8
• Page End: 18
• Publication Date: 2020-03-01
• Subjects: p21-activated kinase 1 -- Tumour microenvironment -- Pancreatic stellate cells -- Programmed death-ligand 1; α-SMA alpha-smooth muscle actin -- ECM extracellular matrix -- IHC immunohistochemistry -- KPC LSL-KrasG12D/+, LSL-Trp53R172H/+, Pdx-1-Cre -- PAK1 p21-activated kinase -- PD-1 programmed death 1 -- PDA pancreatic adenocarcinoma -- PD-L1 programmed death-ligand 1 -- PSC pancreatic stellate cell -- TMA tissue microarray -- TME tumour microenvironment -- TIL tumour infiltrating lymphocyte -- Treg regulatory T cell -- KD knockdown -- KO knockout -- BMI body mass index.; Cancer -- Periodicals; Neoplasms -- Periodicals; Cancer -- Périodiques; Electronic journals; 616.994
• DOI: 10.1016/j.canlet.2019.12.020
• Languages: English
• ISSNs: 0304-3835

Abstract

Abstract: 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. Highlights: Low PAK1 expression is related to reduced tumour growth and better survival. PAK1 regulates the activity of pancreatic stroma and tumour immune response. Deletion of PAK1 decreases PSC-stimulated PDA cell proliferation and migration. PAK1 inhibition reduces intrinsic and PSC-stimulated PD-L1 expression in PDA cells. Inhibition of PAK1 enhances cytotoxic lymphocyte-induced PDA cell death.