Innate Direct Anticancer Effector Function of Human Immature Dendritic Cells. I. Involvement of an Apoptosis-Inducing Pathway

Abstract

Dendritic cells (DCs) mediate cross-priming of tumor-specific T cells by acquiring tumor Ags from dead cancer cells. The process of cross-priming would be most economical and efficient if DCs also induce death of cancer cells. In this study, we demonstrate that normal human in vitro generated immature DCs consistently and efficiently induce apoptosis in cancer cell lines, freshly isolated noncultured cancer cells, and normal proliferating endothelial cells, but not in most normal cells. In addition, in vivo generated noncultured peripheral blood immature DCs mediate similar tumoricidal activity as their in vitro counterpart, indicating that this DC activity might be biologically relevant. In contrast to immature DCs, freshly isolated monocytes (myeloid DC precursors) and in vitro generated mature DCs are not cytotoxic or are less cytotoxic, respectively, suggesting that DC-mediated killing of cancer cells is developmentally regulated. Comparable cytotoxic activity is mediated by untreated DCs, paraformaldehyde-fixed DCs, and soluble products of DCs, and is destructible by proteases, indicating that both cell membrane-bound and secreted proteins mediate this DC function. Overall, our data demonstrate that human immature DCs are capable of inducing apoptosis in cancer cells and thus to both directly mediate anticancer activity and initiate processing of cellular tumor Ags.

Differential effects of G-CSF mobilisation on dendritic cell subsets in normal allogeneic donors and patients undergoing autologous transplantation

“…More recent studies, however, suggest that DC also play an important role, not only in the induction of tolerance, but also as cytotoxic anticancer cells. 19,20 Initial studies suggested these differing functional roles were carried out by distinct DC subsets such as the CD11c + and CD11c Ϫ blood DC identified in humans. 34 However, more recent data have demonstrated that these subsets do in fact have considerable functional plasticity 25,35,36 and their functional and clinical significance therefore remains unclear.…”

“…It has been recently reported that immature but not mature DC are able to directly mediate anti-cancer activity. 19 The presence of elevated numbers of immature DC in PBSC grafts may therefore also have a direct effect on the malignant population.…”

“…18 Although DC have historically been considered as inducers of immune responses, it has become clear that they also play a critical role in the induction of tolerance/ suppression 18 and have also been shown to have anti-cancer cytotoxic activity. 19 The role and potential therapeutic use of DC in modulating immune function is therefore of considerable interest in the fields of transplantation and cancer immunotherapy. 20,21 DC populations are morphologically and phenotypically heterogeneous and in humans two phenotypically distinct subsets of blood DC have been identified based on their differential expression of CD11c and CD123 (CD11c + , CD123 dim 'myeloid' DC and CD11c Ϫ , CD123 + 'lymphoid' DC).…”

The ‘kiss of death’ by dendritic cells to cancer cells

“…72,73 Immature DCs have also been shown to kill freshly isolated tumors. [74][75][76] Although in vitro-derived immature DCs kill target cells very efficiently at low effector/target ratios via an apoptotic mechanism involving DNA fragmentation, mitochondrial dysfunction, and late membrane disruption, the level of cytotoxicity found in the freshly isolated, immature DCs remains low and questionable. 75 To note, while Chen's group 70 demonstrated that the tumor killing by immature DCs is mediated through direct cell-to-cell contact, Vujanovic's group 75 showed, using the same type of immature DCs, that the killing mechanism was mediated by both cell-to-cell contact and soluble mediators.…”

Activated human umbilical cord blood dendritic cells kill tumor cells without damaging normal hematological progenitor cells

“…(9) In addition, based on a series of publications, DC exert selective cytotoxic activity toward tumor cells, while demonstrating no cytotoxicity toward normal cells, such as dermal fibroblasts, epidermal melanocytes, mammary epithelial cells and T cell blasts. (10) We presumed that CBDC could act as effector cells to eliminate residual malignant cells after cord blood transplantation in hematologic malignancies. In direct support of this hypothesis, we obtained novel information that human CBDC are potent and promiscuous anticancer cytotoxic cells, capable of selectively killing hematological tumor cells through up-regulating the cytoplasmic TNF-α-related apoptosis-inducing ligand (TRAIL), without damaging the normal hematopoietic progenitor cells.…”