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.
Keywords:
microsomal prostaglandin E synthase-1; natural killer T cells; pancreatic cancer; prevention; treatment.
© 2017 John Wiley & Sons Ltd.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, N.I.H., Extramural
MeSH terms
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Animals
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Antigens, CD1d / genetics
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Arachidonate 5-Lipoxygenase / immunology
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Arachidonate 5-Lipoxygenase / metabolism
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CD8 Antigens / immunology
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CD8 Antigens / metabolism
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Carcinoma in Situ / genetics
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Carcinoma in Situ / immunology*
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Carcinoma in Situ / metabolism
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Carcinoma in Situ / prevention & control
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Cell Proliferation
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Disease Progression
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Genes, ras
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Genetic Predisposition to Disease
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Humans
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Lipoxygenase Inhibitors / pharmacology
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Macrophages / drug effects
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Macrophages / immunology*
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Macrophages / metabolism
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Mice, Inbred C57BL
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Mice, Knockout
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Natural Killer T-Cells / immunology*
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Natural Killer T-Cells / metabolism
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Neoplastic Stem Cells / immunology
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Neoplastic Stem Cells / pathology
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Pancreatic Neoplasms / genetics
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Pancreatic Neoplasms / immunology*
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Pancreatic Neoplasms / metabolism
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Pancreatic Neoplasms / prevention & control
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Phenotype
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Prostaglandin-E Synthases / antagonists & inhibitors
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Prostaglandin-E Synthases / immunology
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Prostaglandin-E Synthases / metabolism
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Signal Transduction
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T-Lymphocytes, Regulatory / immunology
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T-Lymphocytes, Regulatory / metabolism
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Time Factors
Substances
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Antigens, CD1d
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CD1d antigen, mouse
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CD8 Antigens
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CD8 antigen, alpha chain
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Lipoxygenase Inhibitors
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Arachidonate 5-Lipoxygenase
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ALOX5 protein, human
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PTGES protein, human
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Prostaglandin-E Synthases
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Ptges protein, mouse