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

Authors
  • 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)
Type
Published Article
Journal
Cancer letters
Publication Date
Mar 01, 2020
Volume
472
Pages
8–18
Identifiers
DOI: 10.1016/j.canlet.2019.12.020
PMID: 31857154
Source
Medline
Keywords
Language
English
License
Unknown

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

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