To increase (tumor) vaccine efficacy, there is an urgent need for phenotypic and functional characterization of human dendritic cell (DC) subsets residing in lymphoid tissues. In this study we identified and functionally tested 4 human conventional DC (cDC) subsets within skin-draining sentinel lymph nodes (SLNs) from early-stage melanoma patients. These SLNs were all tumor negative and were removed on average 44 days after excision of the primary melanoma. As such, they were considered representative of steady-state conditions. On comparison with skin-migrated cDC, 2 CD1a ؉ subsets were identified as most likely skin-derived CD11c int Langerhans cells (LC) with intracellular langerin and E-cadherin expression or as CD11c hi dermal DCs with variable expression of langerin. Two other CD1a ؊ LNresiding cDC subsets were characterized as CD14 ؊ BDCA3 hi CD103 ؊ and CD14 ؉ BDCA3 lo CD103 ؉ , respectively. Whereas the CD1a ؉ skin-derived subsets displayed greater levels of phenotypic maturation, they were associated with lower levels of inflammatory cytokine release and were inferior in terms of allogeneic T-cell priming and IFN␥ induction. Thus, despite their higher maturation state, skin-derived cDCs (and LCs in particular) proved inferior T-cell activators compared with the CD1a ؊ cDC subsets residing in melanoma-draining LNs. These observations should be considered in the design of DC-targeting immunotherapies. (Blood. 2011;118(9):2502-2510) IntroductionDendritic cells (DCs) are the most powerful APCs and play critical roles in keeping the balance between immune tolerance and activation. DCs are therefore also important for starting an efficient antitumor immune response and are seen as promising targeting candidates for tumor immunotherapy strategies. 1,2 Current DCbased immunotherapies generally use ex vivo-generated autologous monocyte-derived or CD34 ϩ hematopoietic precursorderived DCs. 2,3 Despite occasionally observed clinical benefits from DC-based vaccination, there is a large gap between the actual and expected efficacy of such trials on the basis of in vivo animal experiments. 4 Many questions remain as to which DC type to use, how to stimulate them, or where best to administer the DCs to achieve vaccination with mature, migratory, and Th1-inducing DCs that provoke an efficient antitumor immune response. [5][6][7] An ever-increasing insight in specialized functions of murine DC subsets is sadly mirrored by a lack of knowledge on how human DCs relate to mouse DCs and whether subsets that have been identified in mice have a (phenotypically different, but functionally equivalent) counterpart in humans. 4,[8][9][10][11] In particular the interrelationship between nonplasmacytoid, conventional DC (cDC) subsets has been obscure, in large part because of their plasticity and dynamic changes in their differentiation and maturation state, which is accompanied by shifts in associated phenotypic markers. 12 In mice, extensive DC-subset analyses have been performed through the use of transgenic models, the ability ...

Melanoma-induced suppression of dendritic cells

ABC transporters were identified originally for their contribution to clinical MDR as a result of their capacity to extrude various unrelated cytotoxic drugs. More recent reports have shown that ABC transporters can play important roles in the development, differentiation, and maturation of immune cells and are involved in migration of immune effector cells to sites of inflammation. Many of the currently identified, endogenous ABC transporter substrates have immunostimulating effects. Increasing the expression of ABC transporters on immune cells and thereby enhancing immune cell development or functionality may be beneficial to immunotherapy in the field of oncology. On the contrary, in the treatment of autoimmune diseases, blockade of these transporters may prove beneficial, as it could dampen disease activity by compromising immune effector cell functions. This review will focus on the expression, regulation, and substrate specificity of ABC transporters in relation to functional activities of immune effector cells and discusses implications for the treatment of cancer on the one hand and autoimmune diseases on the other.

Review of in vivo targeting of tumor antigens to lectin receptors on antigen-presenting cells using antibodies or ligands may improve the antitumor efficacy of vaccines.

Dendritic cells (DC) express the ATP-binding cassette (ABC) transporters P-glycoprotein (ABCB1) and multidrug resistance protein 1 (MRP1; ABCC1). Functionally, both these transporters have been described to be required for efficient DC and T cell migration. In this study, we report that MRP1 activity is also crucial for differentiation of DC. Inhibition of MRP1, but not P-glycoprotein, transporter activity with specific antagonists during in vitro DC differentiation interfered with early DC development. Impaired interstitial and Langerhans DC differentiation was characterized by 1) morphological changes, reflected by dropped side scatter levels in flow cytometric analysis and 2) phenotypic changes illustrated by maintained expression of the monocytic marker CD14, lower expression levels of CD40, CD86, HLA-DR, and a significant decrease in the amount of cells expressing CD1a, CD1c, and Langerin. Defective DC differentiation also resulted in their reduced ability to stimulate allogeneic T cells. We identified the endogenous CD1 ligands sulfatide and monosialoganglioside GM1 as MRP1 substrates, but exogenous addition of these substrates could not restore the defects caused by blocking MRP1 activity during DC differentiation. Although leukotriene C4 was reported to restore migration of murine Mrp1-deficient DC, the effects of MRP1 inhibition on DC differentiation appeared to be independent of the leukotriene pathway. Though MRP1 transporter activity is important for DC differentiation, the relevant MRP1 substrate, which is required for DC differentiation, remains to be identified. Altogether, MRP1 seems to fulfill an important physiological role in DC development and DC functions.