Innate Direct Anticancer Effector Function of Human Immature Dendritic Cells. II. Role of TNF, Lymphotoxin-α1β2, Fas Ligand, and TNF-Related Apoptosis-Inducing Ligand

Abstract

Our recent studies have demonstrated that human immature dendritic cells (DCs) are able to directly and effectively mediate apoptotic killing against a wide array of cultured and freshly-isolated cancer cells without harming normal cells. In the present study, we demonstrate that this tumoricidal activity is mediated by multiple cytotoxic TNF family ligands. We determine that human immature DCs express on their cell surface four different cytotoxic TNF family ligands: TNF, lymphotoxin-α1β2, Fas ligand, and TNF-related apoptosis inducing ligand; while cancer cells express the corresponding death receptors. Disruptions of interactions between the four ligands expressed on DCs and corresponding death-signaling receptors expressed on cancer cells using specific Abs or R:Fc fusion proteins block the cytotoxic activity of DCs directed against cancer cells. The novel findings suggest that DC killing of cancer cells is mediated by the concerted engagement of four TNF family ligands of DCs with corresponding death receptors of cancer cells. Overall, our data demonstrate that DCs are fully equipped for an efficient direct apoptotic killing of cancer cells and suggest that this mechanism may play a critical role in both afferent and efferent anti-tumor immunity.

Mature But Not Immature Fas Ligand (CD95L)-Transduced Human Monocyte-Derived Dendritic Cells Are Protected from Fas-Mediated Apoptosis and Can Be Used as Killer APC

“…This antitumor activity has recently been attributed to expression of multiple cytotoxic TNF family ligands including FasL (46). Using adenoviral vectors encoding murine FasL, we were able to discriminate between expressions of endogenous and transduced FasL.…”

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

“…The finding remains unclear since it contradicts previous findings. 76 Surprisingly, TLR-7/8-activated human blood-derived DCs demonstrated a Ca 2 þ -dependent cytotoxicity toward tumor cells, evoking a granule exocytosis-dependent mechanism. 54 The authors observed that the basal skin carcinoma-infiltrating CD11c þ DCs co-stained for PRF and GZM and DCs isolated from peripheral blood of those cancer patients exhibit cytotoxicity.…”

“…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.…”

“…Furthermore, the cytotoxicity may be a function of DC maturation since LPS or IFN-g enhances the cytotoxicity of DCs, 70 whereas CD40L or TNF-a does not enhance or even abrogate the killing activity. 76 Furthermore, Vidalain et al 73 showed that poly(I:C) stimulation of the monocyte-derived human DCs leads to an increased cytotoxic activity, via type-I IFN-mediated TRAIL upregulation on DCs. Surprisingly, CD40L-activated DCs with no upregulation of TRAIL expression remained cytotoxic to certain types of tumor cells.…”

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

“…In this context, we are interested in analyzing the cytotoxic potential of human CBDC stimulated with LPS or IFN-γ against hematological tumor cell lines, and investigating whether the newly described tumoricidal activity, associated with human CBDC, is mediated by cytotoxic TNF family ligands, as reported previously in peripheral blood or bone marrow cells derived-DC. (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.…”