Journal
FRONTIERS IN IMMUNOLOGY
Volume 4, Issue -, Pages -Publisher
FRONTIERS RESEARCH FOUNDATION
DOI: 10.3389/fimmu.2013.00403
Keywords
dendritic cells; human DC subsets; skin; macrophages; cancer; immune suppression
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Funding
- Netherlands Organization for Scientific Research, NWO VIDI grant [917-956-321]
- Stichting Cancer Center Amsterdam (CCA)
- Dutch Cancer Society [KWF BUIT-4643]
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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.
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