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

Abstract

Background: Only 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. Methods: The 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. Results: Cell 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. Conclusion: This 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.

The Therapeutic Potential of Tackling Tumor-Induced Dendritic Cell Dysfunction in Colorectal Cancer

“…In addition, several studies have concluded that CRC explant tissue-conditioned medium inhibits LPS-induced in vitro DC maturation and function. In these assays, upregulation of costimulatory markers (CD80 and CD86) and PD-L1, and secretion of IL-12 and TNF-a was inhibited, while secretion of IL-10 was potentiated suggesting DCs acquire a tolerogenic phenotype (184)(185)(186)(187). One study even correlated stronger inhibition of DC maturation by CRC-conditioned medium with poorer survival in patients (186).…”

The Protein Secretome Is Altered in Rectal Cancer Tissue Compared to Normal Rectal Tissue, and Alterations in the Secretome Induce Enhanced Innate Immune Responses

“…DCs are antigen-presenting cells capable of inducing a T cell response, and maturation levels have been associated with patient survival and response to targeted therapies in CRC patients [ 38 , 39 ]. It has previously been reported that the TME in CRC causes inhibition of DC maturation [ 40 , 41 ]. On the contrary, however, we found upregulation of DC maturation by the rectal cancer TME, which is in line with results published by Morrissey et al [ 41 ].…”

“…It has previously been reported that the TME in CRC causes inhibition of DC maturation [ 40 , 41 ]. On the contrary, however, we found upregulation of DC maturation by the rectal cancer TME, which is in line with results published by Morrissey et al [ 41 ]. This finding warrants further investigation since it may have important clinical implications in stratifying patients for whom immunotherapy may offer a clinical benefit.…”

The Immune Underpinnings of Barrett’s-Associated Adenocarcinogenesis: a Retrial of Nefarious Immunologic Co-Conspirators

“…66 Comparatively, in other studies, conditioned media from esophageal cancer cell lines was capable of reducing TNFa levels of lipopolysaccharideactivated dendritic cells. 67 This intriguing juxtaposition requires further attention but also necessitates the significant widening of the commercially available EAC cell P3 inflammasome and cytokine release. Pro-IL1b is cleaved by the inflammasome and caspase 1 into its active form, followed by release of both IL1b and TNFa from tissue resident monocytes and macrophages.…”