Clinically applicable CD34+-derived blood dendritic cell subsets exhibit key subset-specific features and potently boost anti-tumor T and NK cell responses
Cancer Immunology Immunotherapy, vol. 70, pp. 3167–3181
Abstract
Abstract Allogeneic stem cell transplantation (alloSCT), following induction chemotherapy, can be curative for hemato-oncology patients due to powerful graft-versus-tumor immunity. However, disease recurrence remains the major cause of treatment failure, emphasizing the need for potent adjuvant immunotherapy. In this regard, dendritic cell (DC) vaccination is highly attractive, as DCs are the key orchestrators of innate and adaptive immunity. Natural DC subsets are postulated to be more powerful compared with monocyte-derived DCs, due to their unique functional properties and cross-talk capacity. Yet, obtaining sufficient numbers of natural DCs, particularly type 1 conventional DCs (cDC1s), is challenging due to low frequencies in human blood. We developed a clinically applicable culture protocol using donor-derived G-CSF mobilized CD34+ hematopoietic progenitor cells (HPCs) for simultaneous generation of high numbers of cDC1s, cDC2s and plasmacytoid DCs (pDCs). Transcriptomic analyses demonstrated that these ex vivo-generated DCs highly resemble their in vivo blood counterparts. In more detail, we demonstrated that the CD141+CLEG9A+ cDC1 subset exhibited key features of in vivo cDC1s, reflected by high expression of co-stimulatory molecules and release of IL-12p70 and TNF-α. Furthermore, cDC1s efficiently primed alloreactive T cells, potently cross-presented long-peptides and boosted expansion of minor histocompatibility antigen-experienced T cells. Moreover, they strongly enhanced NK cell activation, degranulation and anti-leukemic reactivity. Together, we developed a robust culture protocol to generate highly functional blood DC subsets for in vivo application as tailored adjuvant immunotherapy to boost innate and adaptive anti-tumor immunity in alloSCT patients.
Authors 16
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Radboud University Nijmegen · Radboud University Medical Center · Radboud Institute for Molecular Life Sciences
Affiliation as printed
Department of Laboratory Medicine, Laboratory of Hematology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Geert Grooteplein 8, P.O. Box 9101, 6500 HB, Nijmegen, The Netherlands
Department of Laboratory Medicine, Laboratory of Hematology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands
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Radboud University Nijmegen · Radboud University Medical Center · Radboud Institute for Molecular Life Sciences
Affiliation as printed
Department of Laboratory Medicine, Laboratory of Hematology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Geert Grooteplein 8, P.O. Box 9101, 6500 HB, Nijmegen, The Netherlands
Department of Laboratory Medicine, Laboratory of Hematology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands
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Radboud University Nijmegen · Radboud University Medical Center · Radboud Institute for Molecular Life Sciences
Affiliation as printed
Department of Laboratory Medicine, Laboratory of Hematology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Geert Grooteplein 8, P.O. Box 9101, 6500 HB, Nijmegen, The Netherlands
Department of Laboratory Medicine, Laboratory of Hematology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands
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Radboud University Nijmegen · Radboud University Medical Center · Radboud Institute for Molecular Life Sciences
Affiliation as printed
Department of Laboratory Medicine, Laboratory of Hematology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Geert Grooteplein 8, P.O. Box 9101, 6500 HB, Nijmegen, The Netherlands
Department of Laboratory Medicine, Laboratory of Hematology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands
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Radboud University Nijmegen · Radboud University Medical Center · Radboud Institute for Molecular Life Sciences
Affiliation as printed
Department of Laboratory Medicine, Laboratory of Hematology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Geert Grooteplein 8, P.O. Box 9101, 6500 HB, Nijmegen, The Netherlands
Department of Laboratory Medicine, Laboratory of Hematology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands
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Radboud University Nijmegen · Radboud University Medical Center · Radboud Institute for Molecular Life Sciences
Affiliation as printed
Department of Laboratory Medicine, Laboratory of Hematology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Geert Grooteplein 8, P.O. Box 9101, 6500 HB, Nijmegen, The Netherlands
Department of Laboratory Medicine, Laboratory of Hematology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands
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Leiden University Medical Center
Affiliation as printed
Department of Hematology, Leiden University Medical Center, Leiden, The Netherlands
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Leiden University Medical Center
Affiliation as printed
Department of Hematology, Leiden University Medical Center, Leiden, The Netherlands
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The Netherlands Cancer Institute
Affiliation as printed
Genomics Core Facility, The Netherlands Cancer Institute, Amsterdam, The Netherlands
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Leiden University Medical Center
Affiliation as printed
Department of Hematology, Leiden University Medical Center, Leiden, The Netherlands
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Leiden University Medical Center
Affiliation as printed
Department of Immunology and Oncode Institute, Leiden University Medical Center, Leiden, The Netherlands
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Radboud University Medical Center
Affiliation as printed
Department of Hematology, Radboud University Medical Center, Nijmegen, The Netherlands
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Radboud University Nijmegen · Radboud University Medical Center · Radboud Institute for Molecular Life Sciences
Affiliation as printed
Department of Laboratory Medicine, Laboratory of Hematology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Geert Grooteplein 8, P.O. Box 9101, 6500 HB, Nijmegen, The Netherlands
Department of Laboratory Medicine, Laboratory of Hematology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands
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Leiden University Medical Center
Affiliation as printed
Department of Immunology and Oncode Institute, Leiden University Medical Center, Leiden, The Netherlands
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Radboud University Nijmegen · Radboud University Medical Center · Radboud Institute for Molecular Life Sciences
Affiliation as printed
Department of Laboratory Medicine, Laboratory of Hematology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Geert Grooteplein 8, P.O. Box 9101, 6500 HB, Nijmegen, The Netherlands
Department of Laboratory Medicine, Laboratory of Hematology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands
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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 Institute for Molecular Life Sciences, Radboud University Medical Center, Geert Grooteplein 8, P.O. Box 9101, 6500 HB, Nijmegen, The Netherlands. Willemijn.Hobo@radboudumc.nl
Department of Laboratory Medicine, Laboratory of Hematology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands
Cited by 25 stored of 26
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