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.
Highlights
Reviewed by: Muller Fabbri, Keck School of Medicine University of Southern California, USA Veronique Angeli, National University of Singapore, Singapore
Human skin is densely populated with patrolling myeloid cells, such as Langerhans cells (LC) in the epidermal outer layer and various dermal dendritic cell (DDC) subsets and macrophages in the dermal layer [1, 2]
CD1a+ mature LC and DDC subsets have been linked to type-1 T cell mediated immunity, whereas CD14+ immature DDC subsets have been linked to the induction of humoral immunity and expansion of regulatory T cells (Treg) [11, 12]; see Figure 1 for a schematic overview
Summary
Reviewed by: Muller Fabbri, Keck School of Medicine University of Southern California, USA Veronique Angeli, National University of Singapore, Singapore. This was validated in the same study by a comparative assessment of the ex vivo ability of human skin-emigrated LC vs DDC subsets to prime HLA-A2-matched CD8+ T cells against an epitope derived from the MART-1 melanoma antigen [23].
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