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

Oncogene volume 40, pages 6007–6022 (2021)Cite this article

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Abstract

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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Fig. 1: Gene set enrichment analysis (GSEA) of AmpliSeq transcriptome data identifies enrichment for innate immune gene networks/pathways, in particular the TLR family, in PDAC.
Fig. 2: AmpliSeq transcriptome data identifies deregulated expression of specific innate immune TLR family members in PDAC.
Fig. 3: Increased growth responsiveness of human PDAC cell lines to TLR2 ligand stimulation.
Fig. 4: Antibody-mediated therapeutic blockade of TLR2 suppresses the growth potential of human PDAC cell line tumour xenografts.
Fig. 5: Anti-tumour activity of antibody-mediated TLR2 blockade in naïve and humanised patient-derived PDAC xenografts.
Fig. 6: Identification of a 4-gene TLR2 activation signature with prognostic power in PDAC patients.
Fig. 7: Elevated expression and activation of TLR2 confers chemoresistance in PDAC.

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Data availability

The datasets (including accession codes or web links to publicly available datasets) and analyses generated from this current study are available upon reasonable request to the corresponding author.

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Acknowledgements

We are grateful to Angela Vais (Monash Histology Platform, Melbourne, Australia) for immunohistochemistry and immunofluorescence expertise. We also thank Trevor Wilson and Jodee Gould from the MHTP Medical Genomics Facility (Melbourne, Australia) for providing technical expertise and assistance with the AmpliSeq transcriptomics studies, as well as Minoti Apte (University of New South Wales, Australia) for kindly providing human pancreatic stellate cells. We also thank the Australian Pancreatic Cancer Genome Initiative, supported by an Avner Pancreatic Cancer Foundation Grant, for the provision of biospecimens. This work was supported by research grants awarded by the Avner Pancreatic Cancer Foundation and CASS Foundation, as well as the Operational Infrastructure Support Program by the Victorian Government of Australia. BJJ is supported by an NHMRC Senior Medical Research Fellowship.

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Authors and Affiliations

  1. Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research, Clayton, VIC, Australia

    Joanne Lundy, Linden J. Gearing, Alison C. West, Louise McLeod, Virginie Deswaerte, Liang Yu, Paul J. Hertzog, Daniel Croagh & Brendan J. Jenkins

  2. Department of Molecular and Translational Science, Faculty of Medicine, Nursing and Health Sciences, Monash University, Clayton, VIC, Australia

    Joanne Lundy, Linden J. Gearing, Alison C. West, Louise McLeod, Virginie Deswaerte, Liang Yu, Paul J. Hertzog & Brendan J. Jenkins

  3. Department of Surgery (School of Clinical Sciences at Monash Health), Monash University, Clayton, VIC, Australia

    Hugh Gao & Daniel Croagh

  4. The Kinghorn Cancer Centre, Garvan Institute of Medical Research, Darlinghurst, NSW, Australia

    Sean Porazinski & Marina Pajic

  5. St Vincent’s Clinical School, Faculty of Medicine, University of New South Wales, Darlinghurst, NSW, Australia

    Sean Porazinski & Marina Pajic

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Contributions

Conception and design: BJJ. Development of methodology: JL, LJG, DC, BJJ. Human tissue acquisition: DC. Acquisition of data: JL, LJG, LY. Analysis and interpretation of data: JL, LJG, AW, LM, MP, DC, BJJ. Provision of reagents: SP, MP, PJH. Writing and/or revision of the manuscript: JL, LJG, BJJ. Study supervision: DC, BJJ.

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Correspondence to Brendan J. Jenkins.

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Lundy, J., Gearing, L.J., Gao, H. et al. TLR2 activation promotes tumour growth and associates with patient survival and chemotherapy response in pancreatic ductal adenocarcinoma. Oncogene 40, 6007–6022 (2021). https://doi.org/10.1038/s41388-021-01992-2

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