Human CD34+-derived complete plasmacytoid and conventional dendritic cell vaccine effectively induces antigen-specific CD8+ T cell and NK cell responses in vitro and in vivo

Cellular and Molecular Life Sciences, vol. 80, pp. 298

Abstract

Abstract Allogeneic stem cell transplantation (alloSCT) can be curative for hemato-oncology patients due to effective graft-versus-tumor immunity. However, relapse remains the major cause of treatment failure, emphasizing the need for adjuvant immunotherapies. In this regard, post-transplantation dendritic cell (DC) vaccination is a highly interesting strategy to boost graft-versus-tumor responses. Previously, we developed a clinically applicable protocol for simultaneous large-scale generation of end-stage blood DC subsets from donor-derived CD34+ stem cells, including conventional type 1 and 2 DCs (cDC1s and cDC2s), and plasmacytoid DCs (pDCs). In addition, the total cultured end-product (DC-complete vaccine), also contains non-end-stage-DCs (i.e. non-DCs). In this study, we aimed to dissect the phenotypic identity of these non-DCs and their potential immune modulatory functions on the potency of cDCs and pDCs in stimulating tumor-reactive CD8+ T and NK cell responses, in order to obtain rationale for clinical translation of our DC-complete vaccine. The non-DC compartment was heterogeneous and comprised of myeloid progenitors and (immature) granulocyte- and monocyte-like cells. Importantly, non-DCs potentiated toll-like receptor-induced DC maturation, as reflected by increased expression of co-stimulatory molecules and enhanced cDC-derived IL-12 and pDC-derived IFN-α production. Additionally, antigen-specific CD8+ T cells effectively expanded upon DC-complete vaccination in vitro and in vivo. This effect was strongly augmented by non-DCs in an antigen-independent manner. Moreover, non-DCs did not impair in vitro DC-mediated NK cell activation, degranulation nor cytotoxicity. Notably, in vivo i.p. DC-complete vaccination activated i.v. injected NK cells. Together, these data demonstrate that the non-DC compartment potentiates DC-mediated activation and expansion of antigen-specific CD8+ T cells and do not impair NK cell responses in vitro and in vivo. This underscores the rationale for further clinical translation of our CD34+-derived DC-complete vaccine in hemato-oncology patients post alloSCT.

Authors 15

1. Jesper van Eck van der Sluijs

   Radboud University Nijmegen · Radboud University Medical Center · Radboud Institute for Molecular Life Sciences

   Affiliation as printed

   Department of Laboratory Medicine, Laboratory of Hematology, Radboud University Medical Center, Radboud Institute for Molecular Life Sciences, Geert Grooteplein 8, P.O. Box 9101, 6500 HB, Nijmegen, The Netherlands

2. Diede van Ens

   Radboud University Nijmegen · Radboud University Medical Center · Radboud Institute for Molecular Life Sciences

   Affiliation as printed

   Department of Laboratory Medicine, Laboratory of Hematology, Radboud University Medical Center, Radboud Institute for Molecular Life Sciences, Geert Grooteplein 8, P.O. Box 9101, 6500 HB, Nijmegen, The Netherlands

3. Jolanda Brummelman

   Radboud University Nijmegen · Radboud University Medical Center · Radboud Institute for Molecular Life Sciences

   Affiliation as printed

   Department of Laboratory Medicine, Laboratory of Hematology, Radboud University Medical Center, Radboud Institute for Molecular Life Sciences, Geert Grooteplein 8, P.O. Box 9101, 6500 HB, Nijmegen, The Netherlands

4. Daan Heister

   Radboud University Nijmegen · Radboud University Medical Center · Radboud Institute for Molecular Life Sciences

   Affiliation as printed

   Department of Laboratory Medicine, Laboratory of Hematology, Radboud University Medical Center, Radboud Institute for Molecular Life Sciences, Geert Grooteplein 8, P.O. Box 9101, 6500 HB, Nijmegen, The Netherlands

5. Aastha Sareen

   Radboud University Nijmegen · Radboud University Medical Center · Radboud Institute for Molecular Life Sciences

   Affiliation as printed

   Department of Laboratory Medicine, Laboratory of Hematology, Radboud University Medical Center, Radboud Institute for Molecular Life Sciences, Geert Grooteplein 8, P.O. Box 9101, 6500 HB, Nijmegen, The Netherlands

6. Lisa Truijen

   Radboud University Nijmegen · Radboud University Medical Center · Radboud Institute for Molecular Life Sciences

   Affiliation as printed

   Department of Laboratory Medicine, Laboratory of Hematology, Radboud University Medical Center, Radboud Institute for Molecular Life Sciences, Geert Grooteplein 8, P.O. Box 9101, 6500 HB, Nijmegen, The Netherlands

7. Dorette van Ingen Schenau

   Princess Máxima Center

   Affiliation as printed

   Princess Maxima Center for Pediatric Oncology, Utrecht, The Netherlands

8. Mirjam H.M. Heemskerk Aachen Department of Hematology, Leiden University Medical Center

   Leiden University Medical Center

   Affiliation as printed

   Department of Hematology, Leiden University Medical Center, Leiden, The Netherlands

9. Marieke Griffioen Aachen Department of Hematology, Leiden University Medical Center

   Leiden University Medical Center

   Affiliation as printed

   Department of Hematology, Leiden University Medical Center, Leiden, The Netherlands

10. Michel G.D. Kester Aachen Department of Hematology, Leiden University Medical Center

    Leiden University Medical Center

    Affiliation as printed

    Department of Hematology, Leiden University Medical Center, Leiden, The Netherlands

11. Nicolaas PM Schaap

    Radboud University Medical Center

    Affiliation as printed

    Department of Hematology, Radboud University Medical Center, Nijmegen, The Netherlands

12. Joop H. Jansen

    Radboud University Nijmegen · Radboud University Medical Center · Radboud Institute for Molecular Life Sciences

    Affiliation as printed

    Department of Laboratory Medicine, Laboratory of Hematology, Radboud University Medical Center, Radboud Institute for Molecular Life Sciences, Geert Grooteplein 8, P.O. Box 9101, 6500 HB, Nijmegen, The Netherlands

13. Anniek B. van der Waart

    Radboud University Nijmegen · Radboud University Medical Center · Radboud Institute for Molecular Life Sciences

    Affiliation as printed

    Department of Laboratory Medicine, Laboratory of Hematology, Radboud University Medical Center, Radboud Institute for Molecular Life Sciences, Geert Grooteplein 8, P.O. Box 9101, 6500 HB, Nijmegen, The Netherlands

14. Harry Dolstra

    Radboud University Nijmegen · Radboud University Medical Center · Radboud Institute for Molecular Life Sciences

    Affiliation as printed

    Department of Laboratory Medicine, Laboratory of Hematology, Radboud University Medical Center, Radboud Institute for Molecular Life Sciences, Geert Grooteplein 8, P.O. Box 9101, 6500 HB, Nijmegen, The Netherlands

15. Willemijn A. Hobo corresponding

    Radboud University Nijmegen · Radboud University Medical Center · Radboud Institute for Molecular Life Sciences

    Affiliation as printed

    Department of Laboratory Medicine, Laboratory of Hematology, Radboud University Medical Center, Radboud Institute for Molecular Life Sciences, Geert Grooteplein 8, P.O. Box 9101, 6500 HB, Nijmegen, The Netherlands. Willemijn.Hobo@Radboudumc.nl

    Department of Laboratory Medicine, Laboratory of Hematology, Radboud University Medical Center, Radboud Institute for Molecular Life Sciences, Geert Grooteplein 8, P.O. Box 9101, 6500 HB, Nijmegen, The Netherlands