The tumour microenvironment of the upper and lower gastrointestinal tract differentially influences dendritic cell maturation

Maria E Morrissey,Dermot O’Toole,Celina Nulty,Jacintha O’Sullivan,Paul Mccormick,Niamh H Mccabe,Joanne Lysaght,John Larkin,Elizabeth J Ryan,Mary-Clare Cathcart,Róisín Byrne,Clare T Butler,Niamh Lynam-Lennon,Susan Kennedy,Brian Mehigan,Margaret R Dunne,John V Reynolds

doi:10.1186/s12885-020-07012-y

Abstract

BackgroundOnly 10–30% of oesophageal and rectal adenocarcinoma patients treated with neoadjuvant chemoradiotherapy have a complete pathological response. Inflammatory and angiogenic mediators in the tumour microenvironment (TME) may enable evasion of anti-tumour immune responses.MethodsThe TME influence on infiltrating dendritic cells (DCs) was modelled by treating immature monocyte-derived DCs with Tumour Conditioned Media (TCM) from distinct gastrointestinal sites, prior to LPS-induced maturation.ResultsCell line conditioned media from gastrointestinal cell lines inhibited LPS-induced DC markers and TNF-α secretion. TCM generated from human tumour biopsies from oesophageal, rectal and colonic adenocarcinoma induced different effects on LPS-induced DC markers - CD54, CD80, HLA-DR, CD86 and CD83 were enhanced by oesophageal cancer; CD80, CD86 and CD83 were enhanced by rectal cancer, whereas CD54, HLA-DR, CD86, CD83 and PD-L1 were inhibited by colonic cancer. Notably, TCM from all GI cancer types inhibited TNF-α secretion. Additionally, TCM from irradiated biopsies inhibited DC markers. Profiling the TCM showed that IL-2 levels positively correlated with maturation marker CD54, while Ang-2 and bFGF levels negatively correlated with CD54.ConclusionThis study identifies that there are differences in DC maturational capacity induced by the TME of distinct gastrointestinal cancers. This could potentially have implications for anti-tumour immunity and response to radiotherapy.

Highlights

10–30% of oesophageal and rectal adenocarcinoma patients treated with neoadjuvant chemoradiotherapy have a complete pathological response
Differential Dendritic Cell (DC) maturation induced by conditioned media from oesophageal adenocarcinoma (OAC) and Colorectal cancer (CRC) cell lines, while both inhibited Tumor Necrosis Factor-Alpha (TNF-α) secretion We investigated if the maturational capacity of DCs could be influenced by conditioned media harvested from cell lines from upper and lower GI tract cancers
Tumour Conditioned Media (TCM) of 2Gy-irradiated tumour microenvironment (TME) from GI cancers significantly inhibited LPS-induced DC markers As the standard-of-care treatment for oesophageal and rectal cancer includes radiotherapy which influences the immune system through unclear mechanisms, we investigated if the maturational capacity of DCs is influenced by irradiated GI tract cancers

Summary

Introduction

10–30% of oesophageal and rectal adenocarcinoma patients treated with neoadjuvant chemoradiotherapy have a complete pathological response. Epidemiological and scientific studies group colon and rectal cancer together, despite their different standard treatment regimens [3, 4]. Morrissey et al BMC Cancer (2020) 20:566 involves neoadjuvant chemoradiotherapy (CRT) to shrink the tumour prior to surgical resection, whereas for colonic adenocarcinoma the standard treatment involves surgical resection followed by adjuvant targeted therapies [5,6,7]. Response to CRT is highly variable with just 10–30% of patients achieving a complete pathological response, which is linked with higher 5-year survival rates, for both oesophageal and rectal cancer [8,9,10,11,12,13]. Understanding the key components of the immune system which are modulated by the tumour microenvironment (TME) may offer insights into ways to improve the clinical outcome for patients with GI cancers by identifying either prognostic biomarkers or novel therapeutic strategies

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