Activity of TNF‐related apoptosis‐inducing ligand (TRAIL) in haematological malignancies

Abstract

Summary. T-cell cytotoxicity is primarily mediated by two cell surface proteins, Fas ligand (FasL) and tumour necrosis factor-related apoptosis-inducing ligand (TRAIL), and intracellular perforin and granzyme granules. FasL-deficient and perforin-deficient T lymphocytes maintain cytotoxicity but fail to induce graft-versus-host disease (GVHD) when transplanted into mice, suggesting that GVHD and graftversus-tumour (GVT) effects can be dissociated, and that TRAIL is not involved in the pathogenesis of GVHD. Because TRAIL could mediate a favourable GVT effect it became important to study the spectrum of its activity and to investigate factors that can dissociate its expression from FasL. TRAIL induced apoptosis in 11/41 (27%) tumour specimens of haematological origin compared to 16/41 (39%) induced by FasL. Although eight specimens were sensitive to both FasL and TRAIL, no synergism was observed between these two ligands. TRAIL induced apoptosis in a dose and time dependent manner with an ED 50 of 0 . 5 mg/ml and ED max of 1 mg/ml. TRAIL activity was not reduced by the over-expression of the multidrug resistant (MDR) protein, and was not enhanced by 9-cis retinoic acid (RA), which can down-regulate bcl-2 protein. Both ligands were simultaneously up-regulated in normal peripheral blood lymphocytes in response to IL-2, IL-15 and anti-CD3 antibody, whereas IL-10 had no effect. Together, our data show that (1) TRAIL can mediate cell death in a variety of human haematological malignancies, (2) resistance to TRAIL is not mediated by MDR protein, (3) the lack of synergy between TRAIL and FasL suggests that either one is sufficient to mediate T-cell cytotoxicity, and (4) within the panel of cytokines tested, the expression of TRAIL and FasL could not be dissociated.

Prevalence and clinical significance of resistance to perforin- and FAS-mediated cell death in leukemia

“…Although we have not investigated the underlying mechanisms of resistance to FAS ligation, data from these previous reports show that leukemic cells can be insensitive to anti-FAS either by lacking expression of FAS/CD95, secretion of soluble FAS to block the FAS ligand, or low Bax/Bcl-2 ratios, thus preventing apoptosis. [20][21][22] In this study, we found that leukemic cells not only from patients with AML but also from CML were resistant to perforinmediated killing. This suggests that myeloid leukemic cells may show a higher degree of resistance towards perforin compared to lymphoid cells.…”

In vitro susceptibility to TRAIL-induced apoptosis of acute leukemia cells in the context of TRAIL receptor gene expression and constitutive NF-κB activity

“…34,35,39 The independence of CD95 and TRAIL susceptibility is well documented in normal T cells as well as in individual leukemic cell samples. 18,40 To determine whether the expression pattern of TRAIL receptors R1-R4 might explain the rather low TRAIL susceptibility observed, we examined constitutive mRNA levels of these receptors by semi-quantitative RT-PCR. Relative expression levels were heterogeneous, and neither the expression of the signal-transducing TRAIL receptors R1 and R2 nor of the decoy receptors R3 and R4 correlated with TRAIL susceptibility.…”

“…17 TRAIL susceptibility was independent of MDR ('multi-drug resistance') protein overexpression and expression levels of the apoptosis-regulating molecules Bcl-2 and Bax. 18 TRAIL effectively induced apoptosis in multiple myeloma cell lines independently of their Bcl-2 expression levels and was not cytotoxic to CD34 + /CD45 dim hematopoietic stem cells. 19,20 Primary tumor cells of hematopoietic origin constitutively expressed TRAIL and were able to induce TRAIL-mediated apoptosis in Jurkat cells.…”

N-(4-hydroxyphenyl) retinamide (4HPR) enhances TRAIL-mediated apoptosis through enhancement of a mitochondrial-dependent amplification loop in ovarian cancer cell lines

“…6,7 Similar results have been reported in other cancer cell lines. 8,9 Several mechanisms have been described that regulate sensitivity to TRAIL-mediated apoptosis. These include the expression of decoy receptors that bind to TRAIL but do not activate the caspase cascade, 3 the expression of inhibitory downstream molecules such as survivin, 10 FADD-like ICE inhibitory proteins (FLIP), 11,12 and inhibitors of apoptosis (IAPs), 13 and the activation of antiapoptotic transcription factors such as NF-kB.…”