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

  • Wang, Kai1
  • Zhan, Yifan2
  • Huynh, Nhi1
  • Dumesny, Chelsea1
  • Wang, Xiao1
  • Asadi, Khashayer3
  • Herrmann, David4
  • Timpson, Paul4
  • Yang, Yang1
  • Walsh, Katrina1
  • Baldwin, Graham S1
  • Nikfarjam, Mehrdad1
  • He, Hong5
  • 1 Department of Surgery, University of Melbourne, Austin Health, Heidelberg, Victoria, Australia. , (Australia)
  • 2 Immunology Division, The Walter and Eliza Hall Institute for Medical Research, Parkville, Victoria, Australia; Department of Medical Biology, University of Melbourne, Parkville, 3050, Victoria, Australia. , (Australia)
  • 3 Department of Anatomic Pathology, Austin Health, Heidelberg, Victoria, Australia. , (Australia)
  • 4 Invasion & Metastasis Group, Cancer Research Program, The Kinghorn Cancer Centre, Garvan Institute of Medical Research, Darlinghurst, NSW, Australia; St. Vincent's Clinical School, Faculty of Medicine, University of New South Wales, Sydney, New South Wales 2010, Australia. , (Australia)
  • 5 Department of Surgery, University of Melbourne, Austin Health, Heidelberg, Victoria, Australia. Electronic address: [email protected] , (Australia)
Published Article
Cancer letters
Publication Date
Mar 01, 2020
DOI: 10.1016/j.canlet.2019.12.020
PMID: 31857154


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. Copyright © 2019 Elsevier B.V. All rights reserved.

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