title: Hematopoietic stem cell-derived myeloid and plasmacytoid DC-based vaccines are highly potent inducers of tumor-reactive T cell and NK cell responsesex vivo.
abstract: Because of the potent graft-versus-tumor (GVT) effect, allogeneic stem cell transplantation (alloSCT) can be a curative therapy for hematological malignancies. However, relapse remains the most frequent cause of treatment failure, illustrating the necessity for development of adjuvant post-transplant therapies to boost GVT immunity. Dendritic cell (DC) vaccination is a promising strategy in this respect, in particular, where distinct biologic functions of naturally occurring DC subsets, i.e. myeloid DCs (mDCs) and plasmacytoid DCs (pDCs), are harnessed. However, it is challenging to obtain high enough numbers of primary DC subsets from blood for immunotherapy due to their low frequencies. Therefore, we present here anex vivoGMP-compliant cell culture protocol for generating different DC subsets from CD34+hematopoietic stem and progenitor cells (HSPCs) of alloSCT donor origin. High numbers of BDCA1+mDCs and pDCs could be generated, sufficient for multiple vaccination cycles. These HSPC-derived DC subsets were highly potent in inducing antitumor immune responsesin vitro. Notably, HSPC-derived BDCA1+mDCs were superior in eliciting T cell responses. They efficiently primed naïve T cells and robustly expanded patient-derived minor histocompatibility antigen (MiHA)-specific T cells. Though the HSPC-pDCs also efficiently induced T cell responses, they exhibited superior capacity in activating NK cells. pDC-primed NK cells highly upregulated TRAIL and possessed strong cytolytic capacity against tumor cells. Collectively, these findings indicate that HSPC-derived DC vaccines, comprising both mDCs and pDCs, may possess superior potential to boost antitumor immunity post alloSCT, due to their exceptional T cell and NK cell stimulatory capacity.
authors.affiliation: Department of Laboratory Medicine - Laboratory of Hematology, Radboud University Medical Center , Nijmegen, the Netherlands.
authors.forename: Soley
authors.initials: S
authors.lastname: Thordardottir
authors.affiliation: Department of Hematology, Radboud University Medical Center , Nijmegen, the Netherlands.
authors.forename: Nicolaas
authors.initials: N
authors.lastname: Schaap
authors.affiliation: Department of Laboratory Medicine - Laboratory of Hematology, Radboud University Medical Center , Nijmegen, the Netherlands.
authors.forename: Elja
authors.initials: E
authors.lastname: Louer
authors.affiliation: Department of Hematology, Leiden University Medical Center , Leiden, the Netherlands.
authors.forename: Michel G D
authors.initials: MG
authors.lastname: Kester
authors.affiliation: Department of Hematology, Leiden University Medical Center , Leiden, the Netherlands.
authors.forename: J H Frederik
authors.initials: JH
authors.lastname: Falkenburg
authors.affiliation: Department of Laboratory Medicine - Laboratory of Hematology, Radboud University Medical Center , Nijmegen, the Netherlands.
authors.forename: Joop
authors.initials: J
authors.lastname: Jansen
authors.affiliation: Department of Rheumatology and Clinical Immunology, University Medical Center Utrecht, Utrecht, the Netherlands; Laboratory of Translational Immunology, University Medical Center Utrecht, Utrecht, the Netherlands.
authors.forename: Timothy R D
authors.initials: TR
authors.lastname: Radstake
authors.affiliation: Department of Laboratory Medicine - Laboratory of Hematology, Radboud University Medical Center , Nijmegen, the Netherlands.
authors.forename: Willemijn
authors.initials: W
authors.lastname: Hobo
authors.affiliation: Department of Laboratory Medicine - Laboratory of Hematology, Radboud University Medical Center , Nijmegen, the Netherlands.
authors.forename: Harry
authors.initials: H
authors.lastname: Dolstra
keywords: Antitumor immunity; NK cell; T cell; dendritic cells; graft-versus-tumor immunity; hematopoietic stem and progenitor cell; mDC; pDC; vaccination