Inhibition of PAK1 suppresses pancreatic cancer by stimulation of anti-tumour immunity through down-regulation of PD-L1
- Author(s)
- Wang, K; Zhan, Y; Huynh, N; Dumesny, C; Wang, X; Asadi, K; Herrmann, D; Timpson, P; Yang, Y; Walsh, K; Baldwin, GS; Nikfarjam, M; He, H;
- Journal Title
- Cancer Letters
- Publication Type
- Journal Article in press
- Abstract
- Immunotherapies have not yielded significant clinical benefits for pancreatic ductal adenocarcinoma (PDA) because of the existence of an immunosuppressive tumour microenvironment (TME) characterised 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.
- Publisher
- Elsevier
- Research Division(s)
- Immunology
- PubMed ID
- 31857154
- Publisher's Version
- https://doi.org/10.1016/j.canlet.2019.12.020
- Terms of Use/Rights Notice
- Refer to copyright notice on published article.
Creation Date: 2019-12-23 11:50:08
Last Modified: 2019-12-23 11:55:29