Abstract
Simple SummaryOesophagogastric adenocarcinomas (OAC) are cancers of the food pipe and stomach which have a strong link with obesity. Natural killer (NK) cells are assassins of the immune system and are crucial for eliminating cancer. We have shown previously that NK cells are pulled into fat in OAC patients by a signalling protein called fractalkine (CX3CL1). Once in fat, NK cells die or are profoundly altered. This diminishes their ability to kill the tumour. We report that exposure to fat can reduce movement of NK cells towards the tumour. However, if a drug called a CX3CR1 antagonist is used to antagonise the receptor for fractalkine, we can restore NK cell movement towards the tumour. When we activate NK cells with a protein called IL-15, fractalkine can reduce its effect on NK cells. This provides further evidence for using CX3CR1 antagonists to reduce NK cell migration to fat and boost NK cell movement to the tumour.Oesophagogastric adenocarcinomas (OAC) are obesity-associated malignancies, underpinned by severe immune dysregulation. We have previously shown that natural killer (NK) cells preferentially migrate to OAC omentum, where they undergo phenotypic and functional alterations and apoptosis. Furthermore, we have identified the CX3CR1:fractalkine (CX3CL1) pathway as pivotal in their recruitment to omentum. Here, we elucidate whether exposure to the soluble microenvironment of OAC omentum, and in particular fractalkine and IL-15 affects NK cell homing capacity towards oesophageal tumour. Our data uncover diminished NK cell migration towards OAC tumour tissue conditioned media (TCM) following exposure to omental adipose tissue conditioned media (ACM) and reveal that this migration can be rescued with CX3CR1 antagonist E6130. Furthermore, we show that fractalkine has opposing effects on NK cell migration towards TCM, when used alone or in combination with IL-15 and uncover its inhibitory effects on IL-15-mediated stimulation of death receptor ligand expression. Interestingly, treatment with fractalkine and/or IL-15 do not significantly affect NK cell adhesion to MAdCAM-1, despite changes they elicit to the expression of integrin α4β7. This study provides further evidence that CX3CR1 antagonism has therapeutic utility in rescuing NK cells from the deleterious effects of the omentum and fractalkine in OAC, thus limiting their dysfunction.
Highlights
Oesophagogastric adenocarcinomas (OAC) are a group of obesity-associated malignancies which encompass oesophageal, gastric and gastro-oesophageal junctional adenocarcinomas
We have previously identified a population of L-selectin+ CX3CR1+ natural killer (NK) cells in the circulation of OAC patients, which we propose would be amenable to CX3CR1 antagonism and spared from recruitment to the omentum and subsequent loss of L-selectin expression [12]
We report the endocytosis of CX3CR1 on the surface of NK cells is reversible following short-term exposure to fractalkine suggesting that NK cell phenotype can be rescued in OAC (Figure 7)
Summary
Oesophagogastric adenocarcinomas (OAC) are a group of obesity-associated malignancies which encompass oesophageal, gastric and gastro-oesophageal junctional adenocarcinomas. OAC is underpinned by severe immune dysregulation and inflammation [1,2,3]. The 5-year survival rates for oesophageal adenocarcinoma and gastric adenocarcinoma of. 20% and 32%, respectively, are largely due to poor treatment response rates of less than. 30%, meaning new therapeutic options are urgently required for a growing group of cancer patients [4,5,6,7,8]. In the setting of OAC, our group have reported the enhanced recruitment of NK cells to the chemotactic cues from visceral adipose tissue (VAT), the largest depot of which is the omentum [11]
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