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

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 Kras^G12D mice. Loss of NKT cells significantly increased pancreatic intraepithelial neoplasia (Pan IN) 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 Pan IN 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. [ABSTRACT FROM AUTHOR]