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.

Keywords: cancer; dendritic cells; human DC subsets; immune suppression; macrophages; skin.

Figure 1

Overview of the reported T cell differentiation induction abilities of mature Langerhans cells (LC) and CD1a⁺ dermal dendritic cells (DDC) vs. immature CD14⁺ DDC. Abbreviations: DDC, dermal dendritic cell; IL, interleukin; LC, Langerhans cell; Th, T helper cell; Tfh, T follicular helper cell; Treg, T regulatory cell; TGF-β, transforming growth factor – β.

Figure 2

Interference by tumor-associated soluble factors with normal dendritic cell (DC) development through indicated underlying signaling pathways, leads to (trans-)differentiation of CD14⁺ M2-macrophage-like cells with immune-suppressive and tumor growth- and invasion-promoting properties. Photographic inserts illustrate the DC and adherent macrophage-like morphology of human skin-emigrated CD83⁺ and CD14⁺ DC, respectively (magnification 400×). Abbreviations: IL, interleukin; PGE2, prostaglandin-E2.