Desirable cytolytic immune effector cell recruitment by interleukin-15 dendritic cells.

// Heleen H. Van Acker 1 , Ottavio Beretta 2 , Sebastien Anguille 1, 3 , Lien De Caluwe 1, 4 , Angela Papagna 2 , Johan M. Van den Bergh 1 , Yannick Willemen 1 , Herman Goossens 1 , Zwi N. Berneman 1, 3 , Viggo F. Van Tendeloo 1 , Evelien L. Smits 1, 3, 5 , Maria Foti 2, * , Eva Lion 1, 3, * 1 Laboratory of Experimental Hematology, Tumor Immunology Group (TIGR), Vaccine and Infectious Disease Institute (VAXINFECTIO), University of Antwerp, Faculty of Medicine and Health Sciences, Antwerp, Belgium 2 School of Medicine and Surgery, University of Milano-Bicocca, Monza, Italy 3 Center for Cell Therapy and Regenerative Medicine, Antwerp University Hospital, Edegem, Belgium 4 Virology Unit, Department of Biomedical Sciences, Institute of Tropical Medicine, Antwerp, Belgium 5 Center for Oncological Research (CORE), University of Antwerp, Faculty of Medicine and Health Sciences, Antwerp, Belgium * Share senior authorship Correspondence to: Heleen H. Van Acker, email: heleen.vanacker@uantwerp.be Keywords: CCL4-CCR5 signaling, dendritic cell vaccination, γδ T cells, immune cell recruitment, NK cells Received: April 25, 2016      Accepted: January 03, 2017      Published: January 13, 2017 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.