TLR9 ligation in pancreatic stellate cells promotes tumorigenesis

Constantinos P. Zambirinis, Elliot Levie, Susanna Nguy, Antonina Avanzi, Rocky Barilla, Yijie Xu, Lena Seifert, Donnele Daley, Stephanie H. Greco, Michael Deutsch, Saikiran Jonnadula, Alejandro Torres-Hernandez, Daniel Tippens, Smruti Pushalkar, Andrew Eisenthal, Deepak Saxena, Jiyoung Ahn, Cristina Hajdu, Dannielle D. Engle, David TuvesonGeorge Miller

Research output: Contribution to journalArticlepeer-review

Abstract

Modulation of Toll-like receptor (TLR) signaling can have protective or protumorigenic effects on oncogenesis depending on the cancer subtype and on specific inflammatory elements within the tumor milieu. We found that TLR9 is widely expressed early during the course of pancreatic transformation and that TLR9 ligands are ubiquitous within the tumor microenvironment. TLR9 ligation markedly accelerates oncogenesis, whereas TLR9 deletion is protective. We show that TLR9 activation has distinct effects on the epithelial, inflammatory, and fibrogenic cellular subsets in pancreatic carcinoma and plays a central role in cross talk between these compartments. Specifically, TLR9 activation can induce proinflammatory signaling in transformed epithelial cells, but does not elicit oncogene expression or cancer cell proliferation. Conversely, TLR9 ligation induces pancreatic stellate cells (PSCs) to become fibrogenic and secrete chemokines that promote epithelial cell proliferation. TLR9-activated PSCs mediate their protumorigenic effects on the epithelial compartment via CCL11. Additionally, TLR9 has immune-suppressive effects in the tumor microenvironment (TME) via induction of regulatory T cell recruitment and myeloid- derived suppressor cell proliferation. Collectively, our work shows that TLR9 has protumorigenic effects in pancreatic carcinoma which are distinct from its influence in extrapancreatic malignancies and from the mechanistic effects of other TLRs on pancreatic oncogenesis.

Original languageEnglish (US)
Pages (from-to)2077-2094
Number of pages18
JournalJournal of Experimental Medicine
Volume212
Issue number12
DOIs
StatePublished - Nov 16 2015

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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