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.
Highlights
Allogeneic stem cell transplantation, following induction chemotherapy, can be curative for hematooncology patients [1]
We describe for the first time a clinically applicable ex vivo culture protocol that enables simultaneous and reproducible generation of high numbers of plasmacytoid DCs (pDCs), cDC2s and the rare cDC1s from G-CSF mobilized C D34+ hematopoietic progenitor cells (HPCs), derived from donor stem cell grafts
Ex vivo pDCs, cDC2s and cDC1s are simultaneously generated from G‐CSF mobilized CD34+ HPCs and approximate their natural counterparts and heatmap analyses using these differentially expressed genes revealed a high similarity between ex vivo-generated dendritic cell (DC) subsets and their corresponding in vivo counterparts (Fig. 2b)
Summary
Allogeneic stem cell transplantation (alloSCT), following induction chemotherapy, can be curative for hematooncology patients [1]. Donor-derived natural killer (NK) cells play an important role in GVT immunity [3], especially upon KIR-ligand mismatched alloSCTs [4]. Many patients exhibit suboptimal activation, expansion and/or functionality of tumor-reactive T and NK cells, which contributes to relapse. This underscores the medical need for adjuvant immunotherapy. In this regard, dendritic cell (DC) vaccination is highly attractive as DCs are the key orchestrators of innate and adaptive immunity. To increase the potency and therapeutic efficacy of DC vaccination, alternative strategies are actively pursued, including the use of natural human DC subsets due to their unique functional properties and cross-talk capacity [6,7,8]
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