Tylosis with Oesophageal Cancer (TOC) is a rare autosomal dominant syndrome characterised by palmoplantar keratoderma and a high lifetime risk of developing oesophageal squamous cell carcinoma. TOC is associated with gain-of-function mutations in RHBDF2, encoding iRhom2, which regulates the stress-responsive keratin cytoskeleton and the maturation of ADAM17; a major sheddase of several pro-inflammatory cytokines. Thus, we hypothesised that TOC tissue is associated with an aberrant inflammatory milieu. 

Initially, we performed RNAseq on both normal and TOC oesophagus tissue and following analysis with CIBERSORT and xCell, we identified elevated numbers of mast cells and M2 macrophages in TOC biopsies, which is indicative of a type 2 immune response. Moreover, a unique immune transcriptomic signature was associated with TOC oesophagus which contains the alarmins, IL-33 and S100A7, and elevated levels of the type 2-associated transcription factor, GATA-3. 

We then looked within TOC interfollicular skin and identified elevated numbers of CD68+ cells. However, neither M2 macrophages nor mast cells were observed, which suggests that the type 2 immune phenotype observed in TOC oesophagus may be site-specific. Interestingly, S100A7 was elevated in TOC interfollicular skin, which reflects the transcriptomic signature in TOC oesophagus. 

We have evidence that this type 2 response could be regulated by a number of iRhom2-mediated pathways. These include elevated ADAM-17-mediated NOTCH cleavage and increased GATA-3 expression, raised p63 activity and elevated GATA-3 expression, and dysregulated barrier function. Thus, through this study, we hope to determine the mechanistic basis for this immune observation and to elucidate how this contributes to oesophageal dysplasia and hyperproliferative skin conditions.

Type 2 Immunity Linked to iRhom2 and Tylosis with Oesophageal Cancer