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Abstract
The aim of our studies is to determine the dynamics of natural killer (NK) cell modulation in gingivae in precancerous and cancerous stages of pancreatic and oral cancers in P48+/Cre;LSL-KRASG12D (KC) mice carrying a pancreas-specific oncogenic Kras mutation and BLT-humanized mice. Wild type and KC mice fed with control diet (CD) or high-fat calorie diet (HFCD), and the pancreatic and oral tumor-bearing humanized BLT (hu-BLT) mice were used to determine precancerous and cancer induced changes in numbers and function of gingival NK cells. Increased numbers of PanIN lesions and the greatest score of inflammation in pancreas of KC mice fed with CD and HFCD co-related with significant decline in percentages of circulating and gingival NK cells, lack of DX5+ NK expansion and increased secretion of IFN-γ and IL-6 after culture. At the malignant stage of pancreatic cancer, hu-BLT tumor-bearing mice had the lowest secretion of IFN-γ from cells dissociated from the gingival tissues as compared to those from non-tumor-bearing mice. Injection of NK cells into tumor-bearing mice increased IFN-γ secretion, and the secretion was similar or higher than those obtained by gingival cells from non-tumor-bearing hu-BLT control mice. The highest increase in IFN-γ secretion was observed when tumor-bearing mice were fed with AJ2 probiotic bacteria and injected with the NK cells. Along with an increase in secretion of IFN-γ, injection of NK cells in the presence and absence of feeding with AJ2 in pancreatic tumor-bearing mice increased percentages of CD45+ and CD3+ T cells in oral gingival cells. Similar results were observed with oral tumors. In conclusion, these results indicated that oral cavity may mirror systemic disease and provide a rationale for why cancer patients may be prone to suffer from diverse oral pathologies.
Highlights
Natural Killer (NK) cells are large granular lymphocytes that function at the interface of innate and adaptive immunity [1]
At the precancerous stage of tumorigenesis, there is a significant elevation in the secreted inflammatory cytokines by gingival cells in the absence of NK expansion; at the cancerous stage, there is a severe decrease in IFN-γ secretion by the gingival cells from tumor-bearing mice which is restored by a single injection of super-charged NK cells in the presence and absence of feeding with AJ2 probiotic bacteria
We demonstrate that at the precancerous stage of tumorigenesis, there is a significant elevation in the secreted inflammatory cytokines by gingival cells; at the cancerous stage, there is a severe decrease in IFN-γ secretion by the gingival cells from tumor-bearing mice which is restored by a single injection of super-charged NK cells in the presence and absence of feeding with AJ2
Summary
Natural Killer (NK) cells are large granular lymphocytes that function at the interface of innate and adaptive immunity [1]. The majority of murine NK cells express DX5 surface antigen, known as CD49b [5, 6]. We have recently shown that osteoclasts (OCs) are able to significantly expand NK cells, and potently increase NK cell function (coined as super-charged NK cells) due to their superior ability to expand NK cells to kill and secrete IFN-γ and other cytokines allowing for effective targeting of cancer stem cells [10]. Obesity is known to be associated with increased risk of various malignancies [11]. Obesity leading to intra-pancreatic fatty infiltration has been associated with increased risk of pancreatic cancer and its precursor lesions [15]. Excess adiposity and impaired immune function have been described in both humans and genetically obese rodents [16]
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