CCR7+ dendritic cells sorted by binding of CCL19 show enhanced Ag‐presenting capacity and antitumor potency

• Published in: Journal of leukocyte biology Vol. 111; no. 6; pp. 1243 - 1251
• Main Authors: Burgoyne, Paul, Hayes, Alan J, Cooper, Rachel S, Le Brocq, Michelle L, Hansell, Christopher AH, Campbell, John DM, Graham, Gerard J
• Format: Journal Article
• Language: English
• Published: England 01-06-2022
• Subjects: cancer; Cell Movement; cellular therapy; Chemokine CCL19 - metabolism; Chemokine CCL21 - metabolism; chemokines; Chemokines - metabolism; Dendritic Cells; Humans; Lymph Nodes; Receptors, CCR7 - metabolism; translation; vaccines; translation; cancer; cellular therapy; chemokines; vaccines
• ISSN: 0741-5400; 1938-3673
• DOI: 10.1002/JLB.5AB0720-446RR

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.
Graphical
Selection of CCR7+ DCs using chemically synthesized and tagged CCL19 selects a population of DC which improves anti‐tumour immunity and efficacy in solid and metastatic tumour models.