Tumour Tissue Microenvironment Can Inhibit Dendritic Cell Maturation in Colorectal Cancer

Abstract

Inflammatory mediators in the tumour microenvironment promote tumour growth, vascular development and enable evasion of anti-tumour immune responses, by disabling infiltrating dendritic cells. However, the constituents of the tumour microenvironment that directly influence dendritic cell maturation and function are not well characterised. Our aim was to identify tumour-associated inflammatory mediators which influence the function of dendritic cells. Tumour conditioned media obtained from cultured colorectal tumour explant tissue contained high levels of the chemokines CCL2, CXCL1, CXCL5 in addition to VEGF. Pre-treatment of monocyte derived dendritic cells with this tumour conditioned media inhibited the up-regulation of CD86, CD83, CD54 and HLA-DR in response to LPS, enhancing IL-10 while reducing IL-12p70 secretion. We examined if specific individual components of the tumour conditioned media (CCL2, CXCL1, CXCL5) could modulate dendritic cell maturation or cytokine secretion in response to LPS. VEGF was also assessed as it has a suppressive effect on dendritic cell maturation. Pre-treatment of immature dendritic cells with VEGF inhibited LPS induced upregulation of CD80 and CD54, while CXCL1 inhibited HLA-DR. Interestingly, treatment of dendritic cells with CCL2, CXCL1, CXCL5 or VEGF significantly suppressed their ability to secrete IL-12p70 in response to LPS. In addition, dendritic cells treated with a combination of CXCL1 and VEGF secreted less IL-12p70 in response to LPS compared to pre-treatment with either cytokine alone. In conclusion, tumour conditioned media strongly influences dendritic cell maturation and function.

The Trypanosoma brucei gambiense Secretome Impairs Lipopolysaccharide-Induced Maturation, Cytokine Production, and Allostimulatory Capacity of Dendritic Cells

“…Like other professional APCs, DCs also play a central role in antigen presentation and activation of naive T cells, and they both can initiate and modulate immune responses as a function of exogenous stimuli (39). Alteration of DC function is one of the various strategies developed by malignant cells to escape immune elimination (40). In a trypanosome infection, DCs play a crucial role in the activation of Th-cell responses, with DCs being the primary cell population inducing a VSG-specific response in naive T cells (15).…”

Inhibition of Dendritic Cell Maturation by the Tumor Microenvironment Correlates with the Survival of Colorectal Cancer Patients following Bevacizumab Treatment

“…We have previously shown that conditioned media from explant tissue, which more accurately represents the tumor microenvironment including the different cell subtypes within the tumor, inhibit dendritic cell maturation and function (6). We found that TCM of explant tissues inhibit dendritic cell maturation by reducing the expression of CD80, CD54, CD86, HLA-DR, CD1d, and CD83, while also increasing IL-10 and decreasing IL-12p70 secretion.…”

“…All tissue was obtained with the written informed consent of the patient, and the study protocol was approved by the Ethics Committee at St. Vincent's University Hospital. The explanted tissue was cut into 8 equal sized pieces of approximately 5 mm 3 and cultured as previously described (6,13). Briefly, the explanted tumor tissues were either untreated or treated with 100 mg/mL bevacizumab (Avastin) and cultured for 72 hours (in 24-well plates) in 2 mL RPMI-1640 containing 100 U/mL penicillin, 100 mg/mL streptomycin, 4 mg/mL Fungizone, 30 mg/mL gentamicin (Invitrogen), and supplemented with 20% FBS (Invitrogen).…”

“…We have previously shown that the local tumor microenvironment of metastatic colorectal cancer patients contains high levels of the chemokines CXCL1, CXCL5, and CCL2 that have proangiogenic properties. In addition we showed that conditioned media from colorectal cancer ex vivo explant tissue alters dendritic cell maturation and function (6). Dendritic cells are the most important antigen-presenting cells capable of activating naive T cells (7).…”

Immunology and Immunotherapy of Colorectal Cancer

“…However, the role played by DCs in CRC is controversial due to the fact that some studies have found that tumor cells are able to impair the function of these cells in inducing an effective immune response capable of eliminating transformed cells. In this direction, tissue culture media from CRC explants inhibit DC maturation with reduced levels of CD54, CD86, HLA-DR, and CD83, and induce IL-10 secretion while inhibiting secretion of IL-12p70, factors that inhibit Th1 immune responses and probably protect the tumor from a potent immune response [ 125 ]. Moreover, in vivo DCs infi ltrating the tumor show an immature phenotype [ 126 ] and those immature DCs correlate with infi ltration by Treg cells and with no detectable tumor-associated antigen systemic response [ 89 ].…”