Adhesion to substrates induces dendritic cell endothelization and decreases immunological response

Abstract

Dendritic cells (DCs) are antigen presenting cells capable of inducing specific immune responses against microbial infections, transplant antigens, or tumors. DCs have been shown to possess a high plasticity showing different phenotypes in response to their microenvironment. For example, tumor-associated DCs can acquire an angiogenic phenotype thus promoting tumor growth. Further, DCs cultured in vitro under different conditions are able to upregulate the expression of endothelial markers and to express angiogenic factors. Indeed, it has been shown that soluble factors such as VEGF of PGE-2, that are present in the microenvironment of several tumors, affect the biology of these cells. We hypothesize that in addition to soluble factors the adhesion to different substrates will also define the phenotype and function of DCs. Herewith we demonstrate that murine myeloid(m) DCs upregulate endothelial markers such as VE-Cadherin, and to a lesser extent TIE-2, and decrease their immune capabilities when cultured on solid surfaces as compared with the same cells cultured on ultra-low binding (ULB) surfaces. On the other hand, the expression of angiogenic molecules at the level of RNA was not different among these cultures. In order to further investigate this phenomenon we used the murine ID8 model of ovarian cancer which can generate solid tumors when cancer cells are injected subcutaneously or a malignant ascites when they are injected intraperitoneally. This model gave us the unique opportunity to investigate DCs in suspension or attached to solid surfaces under the influence of the same tumor cells. We were able to determine that DCs present in solid tumors showed higher levels of expression of endothelial markers and angiogenic molecules but were not able to respond to inflammatory stimuli at the same extent as DCs recovered from ascites. Moreover, mDCs cultured on ULB surfaces in the presence of tumor factors do not expressed endothelial markers. Taking into account all these data we consider that tumor factors might be responsible for inducing angiogenic properties in DCs, but that in some settings the expression of endothelial markers such as VE-Cadherin and TIE-2 might be a function of attachment to solid surfaces and independent of the angiogenic properties of these cells.

The role of angiogenic growth factors in the immune microenvironment of glioma

“…In some kinds of solid tumors, angiopoietins were reported to be associated with immune cells including TAMs, NK cells and neutrophils, but whether it effects in a similar way in the glioma microenvironment requires further confirmation ( 164 , 165 ). Available evidences showed that Tie2 was expressed in immunocytes including DCs, TAMs, T lymphocytes, neutrophils and mast cells, combining with the findings that ANG2 was expressed aberrantly in gliomas, provide us a feasible theoretical basis for further studying the ANG and immune cell interactions in the glioma microenvironment ( 62 , 166 – 169 ).…”

“…This effect was ascribed to the CCL21-dependent CD8+ T cell activation and DC trafficking ( 61 ). Tumor-associated dendritic cells (TA-DCs) suppress anti-tumor immune responses, but when treated with inflammatory molecules, TA-DCs gain the ability to reactivate T cells ( 62 ).…”

Perspectives on Reprograming Cancer-Associated Dendritic Cells for Anti-Tumor Therapies

“…Upon treatment, the cells regain their ability to activate antigen-specific T cells (10, 49, 50). Considering that cancer-associated DCs can harbor tumor antigen, a compelling strategy would be to reprogram them in vivo .…”

“…The “immune paralysis” of cancer-associated DCs can be overcome in an experimental setting by blocking IL-10R while simultaneously activating specific pattern recognition receptors (PRRs). Upon treatment, the cells regain their ability to activate antigen-specific T cells ( 10 , 49 , 50 ). Considering that cancer-associated DCs can harbor tumor antigen, a compelling strategy would be to reprogram them in vivo .…”

Dendritic cells in autoimmune disorders and cancer of the thyroid

“…A modulation of the host defence into immune settings, supporting or not cancer cell survival, is assumed as one of the most important conditions governing the extend of tumour growth and spreading [66,67]. Numerous tumour specific and tissue damage associated humoral factors attract immune cells and modulate their functional properties [68][69][70][71]. The tumour infiltrating immune cells could serve for example as an important source of angiogenetic factors [72][73][74].…”