Loss of natural killer T cells promotes pancreatic cancer in LSL-KrasG12D/+ mice

Naveena B. Janakiram*, Altaf Mohammed, Taylor Bryant, Rebekah Ritchie, Nicole Stratton, Lydgia Jackson, Stan Lightfoot, Doris M. Benbrook, Adam S. Asch, Mark L. Lang, Chinthalapally V. Rao

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

47 Scopus citations

Abstract

The role of the unique T-cell population, natural killer T (NKT) cells, which have similar functions to NK cells in pancreatic cancer (PC), is not yet evaluated. To address the regulatory roles of NKT cells on tumour progression through tumour-associated macrophages (TAM) and their production of microsomal prostaglandin E synthase-1 (mPGES-1) and 5-lipoxygenase (5-LOX) in (Kras)-driven pancreatic tumour (KPT) progression, we crossed CD1d−/− mice deficient in both invariant and variant NKT cells with the KrasG12D mice. Loss of NKT cells significantly increased pancreatic intraepithelial neoplasia (PanIN) lesions and also increased 5-LOX and mPGES-1 expression in M2-type macrophages and cancer stem-like cells in pancreatic tumours. Pharmacological inhibition of mPGES-1 and 5-LOX in M2 macrophages with specific inhibitor YS-121 in KPT-CD1d−/− mice decreased PanIN lesions and suppressed tumour growth in association with elevated levels of active CD8a cells. Hence, NKT cells regulate PC by modulating TAMs (M2) through mPGES-1 and 5-LOX; and the absence of NKT cells leads to aggressive development of PC.

Original languageEnglish
Pages (from-to)36-51
Number of pages16
JournalImmunology
Volume152
Issue number1
DOIs
StatePublished - Sep 2017
Externally publishedYes

Keywords

  • microsomal prostaglandin E synthase-1
  • natural killer T cells
  • pancreatic cancer
  • prevention
  • treatment

Fingerprint

Dive into the research topics of 'Loss of natural killer T cells promotes pancreatic cancer in LSL-KrasG12D/+ mice'. Together they form a unique fingerprint.

Cite this