Deficiencies in Natural Killer Cell Numbers, Expansion, and Function at the Pre-Neoplastic Stage of Pancreatic Cancer by KRAS Mutation in the Pancreas of Obese Mice

Abstract

The combined/synergistic effect of genetic mutation of KRAS in the pancreas and obesity, a life-style factor on suppression of natural killer (NK) cells at the pre-neoplastic stage of pancreatic cancer has not been investigated and is the subject of this report. Obese mice with KRAS (KC) mutation in the pancreas fed with high-fat calorie diet (HFCD) exhibit severe deficiencies in the NK cell expansion and function at the pre-neoplastic stage of pancreatic cancer. Decreased NK cell-mediated cytotoxicity is observed in the peripheral blood, spleen, pancreas, and peri-pancreatic adipose tissue in obese KC mice, whereas in bone marrow an increased NK cell-mediated cytotoxicity is observed when compared to lean WT mice fed with control diet (CD). Obese KC mice on HFCD demonstrated the least ability to expand NK cells or induce NK cell-mediated cytotoxicity when compared to the other groups of mice. Indeed, the following profile WT/CD > WT/HFCD > KC/CD > KC/HFCD was seen for the ability to expand NK cells or mediate cytotoxicity among four groups of mice in spleen, peripheral blood, pancreas, and peri-pancreatic adipose tissue. Sorted NK cells from the splenocytes of four groups of mice also exhibited the same profiles for the cytotoxicity as the unsorted splenocytes, and a decreased IFN-γ secretion could be seen in cultures of NK cells from KC mice fed with either CD or HFCD. Cultures of NK cells with autologous monocytes from obese KC mice fed with HFCD exhibited decreased cytotoxicity and IFN-γ secretion, whereas cultures of allogeneic NK cells from WT mice fed with CD with osteoclasts of obese mice fed with HFCD demonstrated decreased cytotoxicity but augmented IFN-γ secretion. Increased IL-6 along with decreased IFN-γ and cell-mediated cytotoxicity by the NK cells, within NK-adipose tissue of KC/HFCD mice, may provide safe microenvironment for the expansion of pancreatic tumors.

Obesity-Associated Alterations of Natural Killer Cells and Immunosurveillance of Cancer

“…However, in addition to changes in NK cell number, the expression of the activating NK cell receptors NKp46 and NKG2D in splenic tissue and NKp30 in liver tissue was reduced in diet-induced obese rats, indicating an inhibited activation status of NK cells in obesity (93,143). Moreover, NK cells of obese rodents exhibit a reduced cytotoxicity against tumor cells compared to NK cells isolated from normal weight animals (13,131,140,144). Interestingly, a study using adoptive transfer of NK cells demonstrated that NK cell functionality is dependent on the surrounding metabolic environment as the impaired phenotype of NK cells from obese rats could be ameliorated by transfer of NK cells into normal weight rats.…”

“…Data exist about differences in NK cell numbers in peripheral blood and organs, although the results are conflicting. Numerous studies demonstrated a decrease of the NK cell amount in blood as well as in spleen, lung, and liver of obese rodents (93,98,131,(140)(141)(142)(143). In contrast, other reports exist showing either no changes or an increase of the NK cell number in blood and different tissues of obese individuals (75,93,97,131,132,136,138,142).…”

“…Obese mice with KRAS mutation had a decreased NK cell number in blood, spleen, and bone marrow as well as a reduced NK cell cytotoxicity, compared to their normal weight littermates at the pre-malignant stage of pancreatic tumorigenesis. This has been discussed to contribute to the enhanced progression of cancer from a dysplastic stage to invasive cancer in obese individuals (131).…”

Probiotic-Treated Super-Charged NK Cells Efficiently Clear Poorly Differentiated Pancreatic Tumors in Hu-BLT Mice

“…Patients' NK cells are significantly defective in their function, and the defect is seen at both pre-neoplastic and neoplastic stages of pancreatic cancer [35][36][37]. Patients' NK cells do not recover their full functional potential even when the best activating conditions are provided for their expansion and function [35].…”

Flip‐flops of natural killer cells in autoimmune diseases versus cancers: Immunologic axis

“…Also, peripheral-activated NK cells are considered as biomarkers of response to this treatment method. that the mechanism of NK cell function in tumor environment consists of five steps: (a) being recruited in the tumor, (b) target cell recognition, (c) become activated, (d) downregulate some receptors at the surface level but not at the transcriptional level by a mechanism dependent on the tumor environment, (eof increased IL-6 decreased IFN-γ and cell-mediated cytotoxicity by the NK cells( within NK-adipose tissue of KC/HFCD mice) together, can cause the creation of safe microenvironment for the expansion of pancreatic tumors Kaur et al (2018). Rodrigo Fernandes da SilvaOC HumanIn ovarian cancer-associated ascites, the presence of EOC cells seem to have a role in the impairment of the NK cell response to IL-2 stimulation and create an NK cells, under the influence of Herceptin-coated HER2-overexpressing tumor cells and IL-12 together can produce large amounts of immunostimulatory cytokines, such as IFNγ, TNF-α, MIP-1α, and GMpolyploidy in cancer cells.…”