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

Autor: Yifan Zhan, Mehrdad Nikfarjam, Graham S. Baldwin, Chelsea Dumesny, David Herrmann, Hong S. He, Kai Wang, Paul Timpson, Nhi Huynh, Yang Yang, Xiao Wang, Katrina A Walsh, Khashayer Asadi
Rok vydání: 2019
Předmět:
0301 basic medicine
Adult
CD4-Positive T-Lymphocytes
Male
congenital
hereditary
and neonatal diseases and abnormalities
Cancer Research
health care facilities
manpower
and services
medicine.medical_treatment
T cell
education
Adenocarcinoma
CD8-Positive T-Lymphocytes
B7-H1 Antigen
Disease-Free Survival
03 medical and health sciences
Mice
0302 clinical medicine
Immune system
Lymphocytes
Tumor-Infiltrating
health services administration
Pancreatic cancer
medicine
Tumor Microenvironment
Cytotoxic T cell
Animals
Humans
Aged
Cell Proliferation
Aged
80 and over
Mice
Knockout
Tumor microenvironment
Pancreatic Stellate Cells
Intracellular Signaling Peptides and Proteins
Immunotherapy
Middle Aged
medicine.disease
Gene Expression Regulation
Neoplastic
Disease Models
Animal
030104 developmental biology
medicine.anatomical_structure
Oncology
030220 oncology & carcinogenesis
Cancer research
Hepatic stellate cell
Female
CD8
Carcinoma
Pancreatic Ductal
Zdroj: Cancer letters. 472
ISSN: 1872-7980
Popis: 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.
Databáze: OpenAIRE
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