TNF-Related Apoptosis-Inducing Ligand Mediates Tumoricidal Activity of Human Monocytes Stimulated by Newcastle Disease Virus

Abstract

The Newcastle disease virus (NDV) has antineoplastic and immunostimulatory properties, and it is currently clinically tested in anticancer therapy. However, the tumoricidal mechanisms of NDV tumor therapy are not fully understood. The results presented here demonstrate that NDV-stimulated human monocytes (Mφ) kill various human tumor cell lines and that this tumoricidal activity is mediated by TRAIL. In contrast to soluble TRAIL-R2-Fc, soluble CD95-Fc and TNF-R2-Fc showed only minimal blocking of the antitumor effect. TRAIL expression is induced on human Mφ after stimulation with NDV and UV-inactivated NDV. These results show that TRAIL induction on human Mφ after NDV stimulation is independent from viral replication and that TRAIL mediates the tumoricidal activity of NDV-stimulated human Mφ.

Frontline: Induction of apoptosis and modulation of c‐FLIPL and p53 in immature dendritic cells infected with herpes simplex virus

“…Furthermore, it has been reported that type-I IFN cause rapid maturation of monocytes into TRAIL-expressing DC in SCID mice reconstituted with human PBL [30]. Supporting this concept, TRAIL up-regulation in NDV-infected monocytes could be abrogated by neutralization of type-I IFN [28]. Alternatively, TRAIL gene expression could be induced by viral proteins that activate NF-‹ B as recently demonstrated for the Tax protein of human T cell leukemia virus type I [31].…”

“…In addition, expression of TRAIL was also increased at the protein level. Interestingly, several other viruses have been shown to induce TRAIL in monocytes or monocytederived DC conferring cytotoxicity to these cells: measles virus [26], human cytomegalovirus [27] and Newcastle disease virus (NDV) [28]. This effect could be mediated by virus-induced IFN- § , which has been shown to induce TRAIL expression in DC [29].…”

A tumor vaccine containing anti‐CD3 and anti‐CD28 bispecific antibodies triggers strong and durable antitumor activity in human lymphocytes

“…We previously reported that NDV induces TRAIL on CD14 1 monocytes and on CD3 1 T cells. 13 The cell-mediated antitumor activity observed could therefore at least partially be mediated via TRAIL.…”

“…12 NDV was also shown to induce TNF-related apoptosis inducing ligand (TRAIL), which can mediate tumoricidal activity. 13 To further augment the immunogenicity of the NDVmodified autologous tumor vaccine (ATV-NDV), we constructed 2 bispecific single-chain Fv (bsscFv) antibody molecules that specifically bind to HN molecules and to either CD3 or CD28 molecules on human T lymphocytes. Their construction, production and binding characteristics have been described.…”

Differential Effects of Interleukin-7 and Interleukin-15 on NK Cell Anti-Human Immunodeficiency Virus Activity

“…The findings that (i) NK cells can mediate cytotoxicity by TRAIL (7,32,35,54,63,65,77), (ii) that IL-15 potentiates NK cell cytolytic activity, and (iii) that TRAIL has intrinsic activity against a variety of virally infected targets (5,11,14,17,21,34,41,45,46,73,76) suggest a role for IL-15 to potentiate TRAIL-mediated NK cell viricidal activity. We demonstrate that PBL and resting memory cells from infected individuals express high levels of the TRAIL death receptors and undergo cell death following TRAIL treatments (29,33,45), suggesting that these cells are potential targets for TRAIL killing.…”