| dc.description.abstract | Oesophageal adenocarcinoma (OAC) is characterised as a dismal cancer, with a
5-year survival rate in western countries of less than 20%. The disease is an
inflammation-associated cancer, which can begin as a pre-neoplastic inflammatory
condition known as Barrett’s oesophagus (or Barrett’s metaplasia), progress into
neoplastic dysplasia (pre-malignant cancerous growth of epithelial cells), and then
subsequently to an adenocarcinoma, potentially metastasising further.
The precursor condition, Barrett’s oesophagus, is increasing in incidence, and is
strongly associated with gastro-oesophageal reflux disease (GERD). Metaplasia is
defined as the replacement of a fully differentiated cell type with another
differentiated cell type. Barrett’s metaplasia occurs at the squamo-columnar
junction (SCJ) between the oesophagus and the stomach, due to chronic
inflammation in the lower oesophagus. The metaplastic cells that appear at the
SCJ during Barrett’s oesophagus have an intestinal phenotype, consisting of
terminally differentiated mucus-producing goblet cells, which serve as a
histological marker for the diagnosis of this condition. Dysplastic cells grow
uncontrollably, amounting to irregular crypt sizes and shapes, where there were
previously regular mucus-producing glands composed of terminal goblet cells.
Sometimes these areas of dysplasia progress to an adenocarcinoma.
Caspase-1 is an inflammatory caspase which mediates the maturation and release
of inflammatory cytokines, IL-1β and IL-18, and initiates the inflammatory form of
cell death, pyroptosis, in response to canonical inflammasome activation. A
previous study carried out by our research group characterised the expression of
caspase-1 at different stages of oesophageal disease progression. The study
showed that caspase-1 was significantly upregulated in Barrett’s tissue, mediating
the release of pro-inflammatory cytokines, and contributing to chronic
inflammation, which may act as a mechanism to exacerbate disease. Despite high
caspase-1 expression, IL-18 secretion was found to be significantly lower from
Barrett’s tissue compared to squamous epithelial tissue. IL-18 has been shown to
play anti-tumorigenic roles in the intestine through its immune control over the
microbiome distribution and its role in modulating epithelial homeostasis. Given that Barrett’s cells display intestinal phenotypes, it was hypothesised that IL-18
may be functionally capable of exerting a protective, anti-tumorigenic effect on the
progression of this disease.
This study has gathered evidence to confirm that reduced IL-18 expression occurs
during early disease progression, showing that secreted IL-18 levels are
significantly lower from Barrett’s compared to adjacent normal tissue, though IL-18
secretion increases again from OAC tissue. Secretion of other pro-inflammatory
cytokines like IL-1β, IL-12 and IFN- show a stepwise increase from normal
squamous, to Barrett’s, to OAC tissue. IL-18 expression levels were also shown to
significantly decrease along disease progression using a human cell line model of
disease progression, and a murine model of Barrett’s metaplasia progression.
These results collectively suggest that IL-18 may alleviate early
metaplastic/dysplastic progression, potentially independently of its pro-
inflammatory signalling role, given that opposite trends are seen in expression
levels of IL-12 and IFN-.
This study presents evidence to suggest that stimulation with recombinant IL-18
may exert a direct signalling role on high-grade oesophageal dysplastic cells in
vitro in the form of ERK1/2 activation, which occurred concurrently with increased
wound healing. This is suggestive of a potential pro-tumour effect of the cytokine
during neoplastic progression.
Lastly, this study demonstrated that oesophageal cell lines derived from high-grade
dysplastic tissue and adenocarcinoma tissue secrete high levels of IL-18BP, an
endogenous IL-18 inhibitor, whereas normal squamous or Barrett’s cell do not.
Using bioinformatic analysis of RNAseq data from OAC patients it was observed
that high IL-18BP expression in tumours correlated strongly with immune
checkpoint (IC) expression. This correlation was further demonstrated in vitro
whereby conditioned media from OAC cells stimulated with IFN- (expressing IL-
18BP) caused upregulated TIM-3 and TIGIT expression in NK cells. This suggests
that OAC cells secrete IL-18BP and other factors to upregulate
immunosuppressive mediators in the tumour microenvironment (TME). | en |
