title: Desirable cytolytic immune effector cell recruitment by interleukin-15 dendritic cells.
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.
authors.affiliation: 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.
authors.forename: Heleen H
authors.initials: HH
authors.lastname: Van Acker
authors.affiliation: School of Medicine and Surgery, University of Milano-Bicocca, Monza, Italy.
authors.forename: Ottavio
authors.initials: O
authors.lastname: Beretta
authors.affiliation: 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.|Center for Cell Therapy and Regenerative Medicine, Antwerp University Hospital, Edegem, Belgium.
authors.forename: Sébastien
authors.initials: S
authors.lastname: Anguille
authors.affiliation: 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.|Virology Unit, Department of Biomedical Sciences, Institute of Tropical Medicine, Antwerp, Belgium.
authors.forename: Lien
authors.initials: L
authors.lastname: De Caluwé
authors.affiliation: School of Medicine and Surgery, University of Milano-Bicocca, Monza, Italy.
authors.forename: Angela
authors.initials: A
authors.lastname: Papagna
authors.affiliation: 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.
authors.forename: Johan M
authors.initials: JM
authors.lastname: Van den Bergh
authors.affiliation: 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.
authors.forename: Yannick
authors.initials: Y
authors.lastname: Willemen
authors.affiliation: 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.
authors.forename: Herman
authors.initials: H
authors.lastname: Goossens
authors.affiliation: 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.|Center for Cell Therapy and Regenerative Medicine, Antwerp University Hospital, Edegem, Belgium.
authors.forename: Zwi N
authors.initials: ZN
authors.lastname: Berneman
authors.affiliation: 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.
authors.forename: Viggo F
authors.initials: VF
authors.lastname: Van Tendeloo
authors.affiliation: 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.|Center for Cell Therapy and Regenerative Medicine, Antwerp University Hospital, Edegem, Belgium.|Center for Oncological Research (CORE), University of Antwerp, Faculty of Medicine and Health Sciences, Antwerp, Belgium.
authors.forename: Evelien L
authors.initials: EL
authors.lastname: Smits
authors.affiliation: School of Medicine and Surgery, University of Milano-Bicocca, Monza, Italy.
authors.forename: Maria
authors.initials: M
authors.lastname: Foti
authors.affiliation: 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.|Center for Cell Therapy and Regenerative Medicine, Antwerp University Hospital, Edegem, Belgium.
authors.forename: Eva
authors.initials: E
authors.lastname: Lion
mesh_terms: D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D002465:Cell Movement / Q000276:immunology; D018925:Chemokines / Q000235:genetics / Q000276:immunology; D003713:Dendritic Cells / Q000276:immunology*; D015870:Gene Expression; D006801:Humans; D016219:Immunotherapy, Adoptive / Q000379:methods*; D019409:Interleukin-15 / Q000276:immunology*; D007694:Killer Cells, Natural / Q000276:immunology*; D016692:Receptors, Antigen, T-Cell, gamma-delta / Q000276:immunology; D033921:Vesicular Transport Proteins / Q000276:immunology
chemical_list: D018925:Chemokines; C569274:IL15 protein, human; D019409:Interleukin-15; D016692:Receptors, Antigen, T-Cell, gamma-delta; C488100:TXLNA protein, human; D033921:Vesicular Transport Proteins
keywords: CCL4-CCR5 signaling; NK cells; dendritic cell vaccination; immune cell recruitment; γδ T cells