TLR2 activation promotes tumour growth and associates with patient survival and chemotherapy response in pancreatic ductal adenocarcinoma

Pancreatic ductal adenocarcinoma (PDAC) has an extremely poor prognosis, and is plagued by a paucity of targeted treatment options and tumour resistance to chemotherapeutics. The causal link between chronic inflammation and PDAC suggests that molecular regulators of the immune system promote disease...

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Bibliographic Details
Published in:Oncogene Vol. 40; no. 41; pp. 6007 - 6022
Main Authors: Lundy, Joanne, Gearing, Linden J., Gao, Hugh, West, Alison C., McLeod, Louise, Deswaerte, Virginie, Yu, Liang, Porazinski, Sean, Pajic, Marina, Hertzog, Paul J., Croagh, Daniel, Jenkins, Brendan J.
Format: Journal Article
Language:English
Published: London Nature Publishing Group UK 14.10.2021
Nature Publishing Group
Subjects:
38/1
38/23
38/39
38/77
38/91
45
631/250/262
631/67/1059/2326
631/67/1059/602
631/67/1504/1713
64/60
82/51
Adenocarcinoma
Animals
Apoptosis
Biopsy
Cancer
Carcinoma, Pancreatic Ductal - drug therapy
Carcinoma, Pancreatic Ductal - metabolism
Carcinoma, Pancreatic Ductal - pathology
Care and treatment
Cell Biology
Cell Growth Processes - drug effects
Cell Growth Processes - physiology
Cell Line, Tumor
Cellular signal transduction
Chemoresistance
Chemotherapy
Deoxycytidine - analogs & derivatives
Deoxycytidine - pharmacology
Female
Gemcitabine
Genetic aspects
Health aspects
Human Genetics
Humans
Immune system
Internal Medicine
Medical prognosis
Medicine
Medicine & Public Health
Mice
Mice, Inbred BALB C
Mice, Inbred NOD
Molecular Targeted Therapy
Oncology
Pancreas
Pancreatic cancer
Pancreatic Neoplasms - drug therapy
Pancreatic Neoplasms - metabolism
Pancreatic Neoplasms - pathology
Pancreatic tumors
Patient outcomes
Patients
Precision medicine
Prognosis
Survival
Survival Analysis
Therapeutic targets
TLR2
TLR2 protein
Toll-Like Receptor 2 - antagonists & inhibitors
Toll-Like Receptor 2 - metabolism
Toll-like receptors
Transcriptomes
Tumors
Xenograft Model Antitumor Assays
Xenografts
Australia
ISSN:0950-9232, 1476-5594, 1476-5594
Online Access:Get full text
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Description
Summary:Pancreatic ductal adenocarcinoma (PDAC) has an extremely poor prognosis, and is plagued by a paucity of targeted treatment options and tumour resistance to chemotherapeutics. The causal link between chronic inflammation and PDAC suggests that molecular regulators of the immune system promote disease pathogenesis and/or therapeutic resistance, yet their identity is unclear. Here, we couple endoscopic ultrasound-guided fine-needle aspiration, which captures tumour biopsies from all stages, with whole transcriptome profiling of PDAC patient primary tumours to reveal enrichment of the innate immune Toll-like receptor 2 (TLR2) molecular pathway. Augmented TLR2 expression associated with a 4-gene “TLR2 activation” signature, and was prognostic for survival and predictive for gemcitabine-based chemoresistance. Furthermore, antibody-mediated anti-TLR2 therapy suppressed the growth of human PDAC tumour xenografts, independent of a functional immune system. Our results support TLR2-based therapeutic targeting for precision medicine in PDAC, with further clinical utility that TLR2 activation is prognostic and predictive for chemoresponsiveness.
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ISSN:0950-9232
1476-5594
1476-5594
DOI:10.1038/s41388-021-01992-2