Dendritic Cell Plasticity in Tumor-Conditioned Skin: CD14+ Cells at the Cross-Roads of Immune Activation and Suppression

Abstract

Tumors abuse myeloid plasticity to re-direct dendritic cell (DC) differentiation from T cell stimulatory subsets to immune-suppressive subsets that can interfere with anti-tumor immunity. Lined by a dense network of easily accessible DC the skin is a preferred site for the delivery of DC-targeted vaccines. Various groups have recently been focusing on functional aspects of DC subsets in the skin and how these may be affected by tumor-derived suppressive factors. IL-6, Prostaglandin-E2, and IL-10 were identified as factors in cultures of primary human tumors responsible for the inhibited development and activation of skin DC as well as monocyte-derived DC. IL-10 was found to be uniquely able to convert fully developed DC to immature macrophage-like cells with functional M2 characteristics in a physiologically highly relevant skin explant model in which the phenotypic and functional traits of “crawl-out” DC were studied. Mostly from mouse studies, the JAK2/STAT3 signaling pathway has emerged as a “master switch” of tumor-induced immune suppression. Our lab has additionally identified p38-MAPK as an important signaling element in human DC suppression, and recently validated it as such in ex vivo cultures of single-cell suspensions from melanoma metastases. Through the identification of molecular mechanisms and signaling events that drive myeloid immune suppression in human tumors, more effective DC-targeted cancer vaccines may be designed.

High and Interrelated Rates of PD-L1+CD14+ Antigen-Presenting Cells and Regulatory T Cells Mark the Microenvironment of Metastatic Lymph Nodes from Patients with Cervical Cancer

“…This would also fit with our observation of high levels of IL6 released by single-cell suspensions of LN þ . We and others have reported a phenotypically similar subset in a range of solid tumor types (36)(37)(38)(39). PD-L1 is expressed by the primary cervical tumor cells and its receptor PD-1 is often expressed by T cells infiltrating the primary tumor (40), similar to the results we obtained for LN þ .…”

Disruption of the Blood-Brain Barrier in 22q11.2 Deletion Syndrome

“…We found that following migration across 22qDS+SZ iBBB monolayer, monocytes significantly decreased thrombomodulin (TM, CD141) expression ( Figure 4D-E). As TM is known to be an anti-inflammatory molecule expressed on both immune cells and the luminal endothelium to inhibit immune cell adherence and extravasation (Loghmani & Conway, 2018;van de Ven et al, 2013;Xu et al, 2015), our findings indicate that the 22qDS+SZ BBB has a promigratory effect on immune cells.…”

Tumor stroma-derived factors skew monocyte to dendritic cell differentiation toward a suppressive CD14+PD-L1+phenotype in prostate cancer

“…[30][31][32] IL-6 expression in PCa has been attributed to both stromal and tumor cells 33 and the influences of various tumor-derived factors, such as IL-6 and IL-10, on DC differentiation from myeloid cells have been previously studied. [34][35][36][37] Furthermore, tumor-derived soluble factors have also been shown to affect DC function, 38,39 Fibroblast-derived IL-6 has also previously been shown to effect the differentiation of monocytes into macrophages (rather than DCs). 40,41 However, our experiments clearly demonstrate that in early PCa, IL-6 expression is higher in PCaSt than PCaEp, indicating that stromal cells are the dominant cell type to influence myeloid cell differentiation.…”