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

Author(s): Janakiram NB,  Mohammed A,  Bryant T,  Ritchie R,  Stratton N,  Jackson L,  Lightfoot S,  Benbrook DM,  Asch AS,  Lang ML,  Rao CV

Journal: Immunology

Date: 2017 Sep

Major Program(s) or Research Group(s): CADRG

PubMed ID: 28419443

PMC ID: PMC5543460

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.