Host Absence of CCR5 Potentiates Dendritic Cell Vaccination

Abstract

Previous work has shown that dendritic cells (DCs) express specific chemokine receptors that allow for coordinated movement in vivo. To test the in vivo relevance of this, we used a murine melanoma system and knockout mice to investigate the function of the chemokine receptor CCR5 and its ligands, CCR ligand (CCL)3 and CCL5. We found that the lack of CCR5 in the host mouse resulted in delayed tumor growth, but this effect was overcome at a higher tumor load. With the administration of tumor charged DCs, CCR5−/− mice that had previously been injected with tumor were completely protected from tumor. This effect was dependent on the dose of tumor cells and the expression of CCR5 on the DC and its absence in the host. In contrast, the loss of the CCR5 ligand, CCL3, led to an early delay in tumor growth that did not persist, while the absence of the CCR5 ligand, CCL5, had no effect. Blocking the activity of CCR5 in the host may represent a new strategy for enhancing the activity of a therapeutic melanoma DC vaccine.

Tumor-Infiltrating Monocytic Myeloid-Derived Suppressor Cells Mediate CCR5-Dependent Recruitment of Regulatory T Cells Favoring Tumor Growth

“…In concordance with our results indicating a protumoral role of CCR5/CCR5 ligands in cancer, CCL5 secretion by mesenchymal stem cells enhanced the metastatic potential of breast cancer (46). Ng-Cashin et al (47) demonstrated that the deficiency of CCR5 or its ligand CCL3 resulted in delayed or accelerated melanoma growth depending on the tumor load. Furthermore, in a mouse model of pancreatic adenocarcinoma, knockdown of CCL5 production in tumors resulted in the delayed tumor growth (20).…”

Genetic Protection against Hepatitis B Virus Conferred byCCR5Δ32: Evidence that CCR5 Contributes to Viral Persistence

“…For example, CCR5-deficient mice (ccr5 Ϫ/Ϫ ) infected with Mycobacterium tuberculosis have more dendritic cells in lymph nodes and increased pulmonary inflammation due to a greater T-cell response than ccr5 ϩ/ϩ mice (2). Similar data have been reported for mouse models of Listeria and lymphocytic choriomeningitis virus infections, as well as for enhanced responses to a melanoma dendritic cell vaccine (25,26,39). How CCR5 restrains the immune response is unknown.…”

“…ϩ and CD8 ϩ T-cell responses to a variety of antigens and to a dendritic cell vaccine (25,26,39). Such findings suggest that CCR5 may behave as a negative regulator of T cells in an immune response.…”

Alphaviral vector-transduced dendritic cells are successful therapeutic vaccines against neu-overexpressing tumors in wild-type mice

“…DCs were derived from bone marrow progenitor cells in the presence of GM-CSF and IL-4 [19]. On day 7 of culture, immature DCs were harvested and cryopreserved in 90% FBS/10% DMSO.…”