2. Academic Validation
  3. TLR2 activation promotes tumour growth and associates with patient survival and chemotherapy response in pancreatic ductal adenocarcinoma

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

  • Oncogene. 2021 Oct;40(41):6007-6022. doi: 10.1038/s41388-021-01992-2.
Joanne Lundy 1 2,  Linden J Gearing 1 2,  Hugh Gao 3,  Alison C West 1 2,  Louise McLeod 1 2,  Virginie Deswaerte 1 2,  Liang Yu 1 2,  Sean Porazinski 4 5,  Marina Pajic 4 5,  Paul J Hertzog 1 2,  Daniel Croagh 1 3,  Brendan J Jenkins 6 7
Affiliations

Affiliations

  • 1 Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research, Clayton, VIC, Australia.
  • 2 Department of Molecular and Translational Science, Faculty of Medicine, Nursing and Health Sciences, Monash University, Clayton, VIC, Australia.
  • 3 Department of Surgery (School of Clinical Sciences at Monash Health), Monash University, Clayton, VIC, Australia.
  • 4 The Kinghorn Cancer Centre, Garvan Institute of Medical Research, Darlinghurst, NSW, Australia.
  • 5 St Vincent's Clinical School, Faculty of Medicine, University of New South Wales, Darlinghurst, NSW, Australia.
  • 6 Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research, Clayton, VIC, Australia. Brendan.Jenkins@hudson.org.au.
  • 7 Department of Molecular and Translational Science, Faculty of Medicine, Nursing and Health Sciences, Monash University, Clayton, VIC, Australia. Brendan.Jenkins@hudson.org.au.
PMID: 34400766 DOI: 10.1038/s41388-021-01992-2
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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