Loss of natural killer T cells promotes pancreatic cancer in LSL‐KrasG12D/+ mice. Issue 1 (29th May 2017) - Janakiram, Naveena B.
Summary: 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 (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. Abstract : Loss of natural killer T cells increased mPGES‐1 and 5‐LOX in M2 macrophages thereby increasing pancreatic intraepithelial neoplasia (PanIN) lesions. Inhibition of mPGES‐1 and 5‐LOX decreased PanIN lesions by decreasing regulatory T cells and increasing activity of CD8a cells.