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.
['Wang|Kai|K|', 'Zhan|Yifan|Y|', 'Huynh|Nhi|N|', 'Dumesny|Chelsea|C|', 'Wang|Xiao|X|', 'Asadi|Khashayer|K|', 'Herrmann|David|D|', 'Timpson|Paul|P|', 'Yang|Yang|Y|', 'Walsh|Katrina|K|', 'Baldwin|Graham S|GS|', 'Nikfarjam|Mehrdad|M|', 'He|Hong|H|']
D000230:Adenocarcinoma D000328:Adult D000368:Aged D000369:Aged, 80 and over D000818:Animals D060890:B7-H1 Antigen D015496:CD4-Positive T-Lymphocytes D018414:CD8-Positive T-Lymphocytes D021441:Carcinoma, Pancreatic Ductal D049109:Cell Proliferation D004195:Disease Models, Animal D018572:Disease-Free Survival D005260:Female D015972:Gene Expression Regulation, Neoplastic D006801:Humans D007167:Immunotherapy D047908:Intracellular Signaling Peptides and Proteins D016246:Lymphocytes, Tumor-Infiltrating D008297:Male D051379:Mice D018345:Mice, Knockout D008875:Middle Aged D058954:Pancreatic Stellate Cells D059016:Tumor Microenvironment
Tumour microenvironment Pancreatic stellate cells Programmed death-ligand 1 p21-activated kinase 1