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Dendritic cell therapy has been a promising addition to the current armory of therapeutic options in cancer for more than 20 years but has not yet achieved breakthrough success. To successfully initiate immunity, dendritic cells have to enter the lymph nodes. However, experience to date of therapeutic dendritic cell administration indicates that this is frequently an extremely inefficient process. The major regulator of dendritic cell migration to the lymph nodes is the chemokine receptor CCR7 and in vitro generated dendritic cells typically display heterogeneous expression of this receptor. Here we demonstrate that positive selection for the dendritic cell subpopulation expressing CCR7, using a chemically‐synthesized ligand:CCL19, enriches for cells with enhanced lymph node migration and Ag presentation competence as well as a chemokine expression profile indicative of improved interactions with T cells. This enhanced lymph node homing capacity of enriched CCR7+ cells is seen in comparison to a population of unsorted dendritic cells containing an equivalent number of CCR7+ dendritic cells. Importantly, this indicates that separating the CCR7+ dendritic cells from the CCR7− cells, rather than simple CCL19 exposure, is required to affect the enhanced lymph node migration of the CCR7+ cells. In models of both subcutaneous and metastatic melanoma, we demonstrate that the dendritic cells sorted for CCR7 expression trigger enhanced CD8 T‐cell driven antitumor immune responses which correlate with reduced tumor burden and increased survival. Finally, we demonstrate that this approach is directly translatable to human dendritic cell therapy using the same reagents coupled with clinical‐grade flow‐cytometric sorting. [ABSTRACT FROM AUTHOR]

Chemokines and their receptors are essential regulators of in vivo leukocyte migration and, some years ago, a systematic nomenclature system was developed for the chemokine receptor family. Chemokine receptor biology and biochemistry was recently extensively reviewed. In this review, we also highlighted a new component to the nomenclature system that incorporates receptors previously known as 'scavenging', or 'decoy', chemokine receptors on the basis of their lack of classical signalling responses to ligand binding and their general ability to scavenge, or sequester, their cognate chemokine ligands. These molecules are now collectively referred to as 'atypical chemokine receptors', or ACKRs, and play fundamental roles in regulating in vivo responses to chemokines. This commentary highlights this new addition to the chemokine receptor nomenclature system and provides brief information on the four receptors currently covered by this nomenclature. [ABSTRACT FROM AUTHOR]

The chemokine-scavenging receptor, D6, is reported to regulate resolution of inflammatory responses. However, recent data also point to an unanticipated role for D6 in coordinating innate and adaptive immune responses. Here, we propose that D6 is essential for preventing inflammatory leukocyte association with lymphatic vasculature. In the absence of D6, inappropriate inflammatory leukocyte accumulation around lymphatic endothelium congests the lymphatic system, impairing fluid and cellular flow from inflamed sites to lymph nodes and reducing efficiency of antigen presentation. Thus, the inability of D6-deficient mice to resolve inflammation may be a byproduct of impaired fluid drainage from inflamed sites and thus we provide a model unifying D6 function in innate and adaptive immune responses. [Copyright &y& Elsevier]

Chemokines have been shown to be essential players in a range of cancer contexts. In this study, we demonstrate that mice deficient in the atypical chemokine receptor Ackr2 display impaired development of metastasis in vivo in both cell line and spontaneous models. Further analysis reveals that this relates to increased expression of the chemokine receptor CCR2, specifically by KLRG1+ NK cells from the Ackr-/- mice. This leads to increased recruitment of KLRG1+ NK cells to CCL2-expressing tumors and enhanced tumor killing. Together, these data indicate that Ackr2 limits the expression of CCR2 on NK cells and restricts their tumoricidal activity. Our data have important implications for our understanding of the roles for chemokines in the metastatic process and highlight Ackr2 and CCR2 as potentially manipulable therapeutic targets in metastasis. [ABSTRACT FROM AUTHOR]

Chemokines, acting on their cognate receptors on infiltrating leukocytes, drive the inflammatory response. We have been interested in determining roles and potential mechanisms for the atypical chemokine-scavenging receptor D6 in the regulation of inflammation. In this study, we show that a psoriasis-like pathology that arises in inflamed skins of D6-deficient mice is characterized by a massive and aberrant localization of neutrophils to the dermal/epidermal junction, which is associated with development of the pathology. Such misplacement of neutrophils is also seen with D6-deficient mice in other inflammatory models, suggesting a role for D6 in the spatial positioning of neutrophils within inflamed sites. We further show that D6 functions cell autonomously in this context and that D6, expressed by neutrophils, limits their migrational responses to CCR1 ligands such as CCL3. Our data therefore indicate that D6 is able to play a cell-autonomous role as a migratory rheostat restricting migration of D6-expressing cells such as neutrophils toward ligands for coexpressed inflammatory chemokine receptors. These data have important implications for our understanding of the roles for D6 in regulating inflammation and for our understanding of the control of spatial positioning of leukocytes at inflamed sites. [ABSTRACT FROM AUTHOR]

Lymphatic endothelial cells are important for efficient flow of antigen-bearing fluid and antigen-presenting cells (APC5) from peripheral sites to lymph nodes (LN5). APC movement to LNs is dependent on the constitutive chemokine receptor CCR7, although how conflicting inflammatory and constitutive chemokine cues are integrated at lymphatic surfaces during this process is not understood. Here we reveal a previously unrecognized aspect of the regulation of this process. The D6 chemokine-scavenging receptor, which is expressed on lymphatic endothelial cells (LEC5), maintains lymphatic surfaces free of inflammatory CC-chemokines and minimizes interaction of inflammatory leukocytes with these surfaces. D6 does not alter the level of CCR7 ligands on LEC5, thus ensuring selective presentation of homeostatic chemokines for interaction with CCR7+APC5. Accordingly, in D6deficient mice, inflammatory CC chemokine adherence to LEC5 results in inappropriate perilymphatic accumulation of inflammatory leukocytes at peripheral inflamed sites and draining LNs. This results in lymphatic congestion and impaired movement of APC5, and fluid, from inflamed sites to LNs. We propose that D6, by suppressing inflammatory chemokine binding to lymphatic surfaces, and thereby preventing inappropriate inflammatory leukocyte adherence, is a key regulator of lymphatic function and a novel, and indispensable, contributor to the integration of innate and adaptive immune responses. [ABSTRACT FROM AUTHOR]