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Clinically applicable CD34+-derived blood dendritic cell subsets exhibit key subset-specific features and potently boost anti-tumor T and NK cell responses

Authors :
van Eck van der Sluijs, Jesper
van Ens, Diede
Thordardottir, Soley
Vodegel, Denise
Hermens, Inge
van der Waart, Anniek B.
Falkenburg, J. H. Frederik
Kester, Michel G. D.
de Rink, Iris
Heemskerk, Mirjam H. M.
Borst, Jannie
Schaap, Nicolaas P. M.
Jansen, Joop H.
Xiao, Yanling
Dolstra, Harry
Hobo, Willemijn
Source :
Cancer Immunology Immunotherapy, 70, 11, pp. 3167-3181, Cancer Immunology, Immunotherapy, 70, 3167-3181. SPRINGER, Cancer Immunology, Immunotherapy, Cancer Immunology Immunotherapy, 70, 3167-3181
Publication Year :
2021
Publisher :
Springer Science and Business Media LLC, 2021.

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.

Details

ISSN :
14320851 and 03407004
Volume :
70
Database :
OpenAIRE
Journal :
Cancer Immunology, Immunotherapy
Accession number :
edsair.doi.dedup.....40bb21c842e1ed76bcbe581dc3ed9e03