PO-388 The gastrointestinal tract tumour microenvironment differentially influences maturation of and cytokine secretion from dendritic cells

Abstract

IntroductionOesophageal adenocarcinoma (OAC) and rectal adenocarcinoma are treated with neoadjuvant chemoradiotherapy in order to reduce tumour size prior to surgery however only 10%–30% of patients have a complete pathological response. Inflammatory and angiogenic mediators in the tumour microenvironment (TME) have many functions, such as enabling evasion of anti-tumour immune responses by disabling infiltrating dendritic cells (DCs) and have been linked with radioresistance. Tumour Conditioned Media (TCM) from colonic cancer has been shown to strongly inhibit DC maturation. Our aim was to understand if this DC inhibition extends to other cancers of the gastrointestinal tract, to investigate if radiotherapy influences this and to profile constituents of TCM that may influence DC maturation.Material and methodsTCM from 0Gy or 2Gy-irradiated cell lines or tumour biopsy explants, was used to pre-treat monocyte-derived DCs prior to stimulation with LPS to measure DC maturation based on DC cell surface markers (HLA-DR, CD86, CD54, CD80, CD83 and PD-L1) and two cytokine levels (IL12 p70 and TNF alpha). Inflammatory and angiogenic mediator multiplex ELISAs were used to profile the TCM of oesophageal and rectal adenocarcinoma.Results and discussionsDCs remained responsive to LPS following pre-treatment with OAC cell line TCM, whereas extensive inhibition was induced by CRC cell line TCM. ex vivo TCM from different gastrointestinal adenocarinoma types induced different effects on DC maturation with oesophageal inducing DC activation, rectal inducing minor activation and colonic inducing inhibition of DC maturation markers. Interestingly, all cancer types induced DC inhibition of secreted TNF alpha. It was also found that 2Gy-irradiated TME induced significant inhibition of DC maturation for irradiated rectal adenocarcinoma and no effect with irradiated oesophageal cancer. Differential levels of inflammatory (IL2) and angiogenic mediators (Ang2 and bFGF) in TCM of GI tumours correlated with DC maturation.ConclusionOverall, this study offers new evidence that there are differences in the human TME from different gastrointestinal (GI) cancers which can directly induce varying levels of inhibition of LPS-induced DC maturation markers, whilst all inhibit secreted TNF alpha.