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
  • 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. [email protected].
  • 7. Department of Molecular and Translational Science, Faculty of Medicine, Nursing and Health Sciences, Monash University, Clayton, VIC, Australia. [email protected].
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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