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

Sluijs, J.V. van der; Ens, D. van; Brummelman, J.; Heister, D.; Sareen, A.; Truijen, L.; ... ; Hobo, W. (2023)

Article / Letter to editor

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-alpha 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.

• CD34(+) progenitor cells
• Immunotherapy
• Dendritic cells
• Vaccination
• T cells
• NK cells

• All authors: Sluijs, J.V. van der; Ens, D. van; Brummelman, J.; Heister, D.; Sareen, A.; Truijen, L.; Schenau, D.S.V.I.; Heemskerk, M.H.M.; Griffioen, M.; Kester, M.G.D.; Schaap, N.P.M.; Jansen, J.H.; Waart, A.B. van der; Dolstra, H.; Hobo, W.
• Date: 2023-10-01
• Journal: Cellular and Molecular Life Sciences
• Volume: 80
• Issue: 10
• DOI: doi:10.1007/s00018-023-04923-4