Abstract
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.
Highlights
Cellular therapy is an increasingly important treatment option in a range of clinical contexts including cancers and inflammatory/immune disorders.[1,2,3] success is often limited by the mixed ability of the cells to home to, or be retained in, appropriate in vivo “therapeutic” sites
One of the classic paradigms for chemokine receptor involvement in cellular homing focuses on CCR7,9 which is essential for cellular homing to, and positioning within, lymph nodes (LNs).[10]
Overexpression of CCR7 in dendritic cell (DC) in murine models has been clearly linked with increased LN homing[11,12] and in human cancer patients, the extent of CCR7 expression on DCs correlates with the magnitude of the tumor-infiltrating lymphocyte population.[13]
Summary
Cellular therapy is an increasingly important treatment option in a range of clinical contexts including cancers and inflammatory/immune disorders.[1,2,3] success is often limited by the mixed ability of the cells to home to, or be retained in, appropriate in vivo “therapeutic” sites. We have developed a novel approach to help address this issue.[17] While DC populations generated in vitro for therapeutic purposes invariably express heterogeneous levels of CCR7, we have shown that selection of the subpopulation expressing CCR7 leads to a ‘fitter’ cellular product with enhanced LN homing. Such cell-selection would be carried out using Abs but high-quality Abs are not available for the majority of chemokine receptors. This study demonstrates the value of preselection of DCs for LN homing potential and highlights a potentially important novel development for therapeutic approaches to DC use in cancer vaccinology
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