Abstract
Success of dendritic cell (DC) therapy in treating malignancies is depending on the DC capacity to attract immune effector cells, considering their reciprocal crosstalk is partially regulated by cell-contact-dependent mechanisms. Although critical for therapeutic efficacy, immune cell recruitment is a largely overlooked aspect regarding optimization of DC vaccination. In this paper we have made a head-to-head comparison of interleukin (IL)-15-cultured DCs and conventional IL-4-cultured DCs with regard to their proficiency in the recruitment of (innate) immune effector cells. Here, we demonstrate that IL-4 DCs are suboptimal in attracting effector lymphocytes, while IL15 DCs provide a favorable chemokine milieu for recruiting CD8+ T cells, natural killer (NK) cells and gamma delta (γδ) T cells. Gene expression analysis revealed that IL-15 DCs exhibit a high expression of chemokines involved in antitumor immune effector cell attraction, while IL-4 DCs display a more immunoregulatory profile characterized by the expression of Th2 and regulatory T cell-attracting chemokines. This is confirmed by functional data indicating an enhanced recruitment of granzyme B+ effector lymphocytes by IL-15 DCs, as compared to IL-4 DCs, and subsequent superior killing of tumor cells by the migrated lymphocytes. Elevated CCL4 gene expression in IL-15 DCs and lowered CCR5 expression on both migrated γδ T cells and NK cells, led to validation of increased CCL4 secretion by IL15 DCs. Moreover, neutralization of CCR5 prior to migration resulted in an important inhibition of γδ T cell and NK cell recruitment by IL-15 DCs. These findings further underscore the strong immunotherapeutic potential of IL-15 DCs.
Highlights
Active immunotherapy using tumor antigen-loaded dendritic cells (DCs) for anticancer vaccination has been under extensive investigation the past 20 years, and is currently being tested in among other phase 3 clinical trials [1]
To explore the migratory capacity of immune cells towards chemoattractant agents secreted by IL-15 DCs and IL-4 DCs, a three-hour migration assay towards 48-hour wash-out supernatant of autologous activated DCs was performed
Immunophenotyping of the migrated cells demonstrated that both CD8+ T cells and γδ T cells were significantly more recruited by IL-15 DCs in comparison with the IL-4 DCs (Figure 1 and Supplementary Figure 1A)
Summary
Active immunotherapy using tumor antigen-loaded dendritic cells (DCs) for anticancer vaccination has been under extensive investigation the past 20 years, and is currently being tested in among other phase 3 clinical trials [1]. DCs are sublime professional antigen-presenting cells, which can conveniently be manufactured from monocytes for therapeutic purposes. As a vaccine, they can enhance or induce de novo antitumor immune responses in cancer patients. The most widely adopted protocol generates so-called interleukin (IL)-4 DCs www.impactjournals.com/oncotarget [2]. These monocyte-derived DCs are generated in the presence of granulocyte macrophage colony-stimulating factor and IL-4 for five days, followed by an activation step of two days with the Jonuleit cocktail consisting of the pro-inflammatory cytokines tumor necrosis factor-α, IL-1β, IL-6 and prostaglandin E2 [2]. Overall objective responses and survival benefits are, undeniably present and comparable to some classic treatment strategies, considered rather modest [1]
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