Inhibition of PAK1 suppresses pancreatic cancer by stimulation of anti-tumour immunity through down-regulation of PD-L1
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.
|ISBN||1872-7980 (Electronic) 0304-3835 (Linking)|
|Authors||Wang, K.; Zhan, Y.; Huynh, N.; Dumesny, C.; Wang, X.; Asadi, K.; Herrmann, D.; Timpson, P.; Yang, Y.; Walsh, K.; Baldwin, G. S.; Nikfarjam, M.; He, H.|
|Responsible Garvan Author|
|Publisher Name||CANCER LETTERS|
|URL link to publisher's version||https://www.ncbi.nlm.nih.gov/pubmed/31857154|
|OpenAccess link to author's accepted manuscript version||https://publications.gimr.garvan.org.au/open-access/15333|