Cutting Edge: TRAIL Deficiency Accelerates Hematological Malignancies

Zerafa, Nadeen; Westwood, Jennifer A.; Cretney, Erika; Mitchell, Sally; Waring, Paul; Iezzi, Manuela; Smyth, Mark J.

doi:10.4049/jimmunol.175.9.5586

Cited by 146 publications

(127 citation statements)

References 24 publications

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“…4T1.2, NIH 3T3, and P815 cells have been described (19). ErbB-2/neuT tumor lines were generated as described (34). Briefly, lobular breast carcinomas were excised from 20-to 23-week-old female BALB/c MMTV-ErbB-2/neuT transgenic mice and digested with DNase I and collagenase.…”

Section: Methodsmentioning

confidence: 99%

Antibodies targeted to TRAIL receptor-2 and ErbB-2 synergize in vivo and induce an antitumor immune response

Stagg

Sharkey

Pommey

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

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Despite the development of human epidermal growth factor receptor-2 (ErbB-2/HER2)-targeted therapies, there remains an unmet medical need for breast cancer patients with ErbB-2 overexpression. We investigated the therapeutic activity of an agonist mAb to mouse tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) receptor-2 (DR5) against ErbB2-driven breast cancer. Established tumors in BALB/c transgenic mice expressing a constitutively active ErbB-2/neuT were treated with anti-DR5 mAb and/or anti-ErbB-2 mAb and monitored for tumor progression. Treatment with anti-DR5 or anti-ErbB2 mAb as single agents significantly delayed tumor growth, although all tumors eventually progressed. Remarkably, treatment with a combination of anti-DR5 and anti-ErbB-2 mAbs induced complete response in a majority of mice. In vivo blockade of CD11b ؉ cells, but not natural killer cell depletion, significantly abrogated the early antitumor response. Notably, depletion of CD8 ؉ T cells provoked primary and secondary tumor relapse, revealing the induction of antitumor immunity by the combination treatment. Combined therapy with anti-DR5 and anti-ErbB-2 mAbs further significantly suppressed the growth of advanced spontaneous tumors in ErbB-2/neuT transgenic mice, even when treatment was delayed until tumors were palpable. We thus demonstrated that the combination of anti-DR5 and anti-ErbB2 mAbs might be an effective form of treatment for ErbB-2-overexpressing breast cancer.apoptosis ͉ breast cancer ͉ herceptin ͉ immunity H uman epidermal growth factor receptor-2 (ErbB-2/HER2) is overexpressed in 20-30% of patients with breast cancer and is associated with a poor prognosis (1). The use of trastuzumab (Herceptin; Genentech), a mAb that blocks the activity of ErbB-2, in combination with chemotherapy has been associated with an increased median survival in patients with advanced ErbB-2-positive breast cancer (2-4). In addition to its inhibitory effect on ErbB-2 signaling, trastuzumab mediates its therapeutic effect through the recruitment of immune cells such as monocytes and natural killer (NK) cells (1, 5). Accordingly, trastuzumab-like mAb unable to bind Fc receptors has less therapeutic activity (6), and complete or partial remission induced by trastuzumab correlates with higher antibody-dependent cell cytotoxicity (7-9).Although the development of trastuzumab constitute a major advance in the treatment of ErbB-2-overexpressing breast cancer, there remains an unmet medical need for new therapies. Proapoptotic receptor agonists (PARAs), including recombinant Apo2L/ tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and mAbs, have now emerged as promising anticancer agents (10, 11). PARAs exploit the enhanced susceptibility of cancer cells versus nontransformed cells to TRAIL-mediated apoptosis. Activation of TRAIL-R1 (DR4) or TRAIL-R2 (DR5) triggers the formation of a death-inducing signaling complex (DISC) that activates caspase-8. In some cells (type I), the activation of the ensuing caspase cascade is sufficient t...

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Section: Methodsmentioning

confidence: 99%

Antibodies targeted to TRAIL receptor-2 and ErbB-2 synergize in vivo and induce an antitumor immune response

Stagg

Sharkey

Pommey

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

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“…Both TRAILand TRAIL receptor-deficient animals display increased susceptibility to tumor metastasis [10,11]. It has been reported that TRAIL deficiency leads to autoimmune disease progression, as well as to defects in thymocyte negative selection, although the latter finding is controversial [12,13].…”

Section: Introductionmentioning

confidence: 98%

TRAIL receptor mediates inflammatory cytokine release in an NF-κB-dependent manner

et al. 2009

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In the present article, we report that DR4 or DR5 overexpression dramatically activates the release of the inflammatory cytokines IL-8, TNF-α, CCL20, MIP-2 and MIP-1β in an NF-κB-dependent manner in 293T, MDA-MB-231 and HCT-116 cells. We showed that death receptor-mediated signals were extracellular domain-independent, whereas the effect of overexpression of the DR4 intracellular domain was much less potent. The TRADD-TRAF2-NIK-IKKα/β signaling cascade, which plays an essential role in TNF-induced NF-κB activation, was found to be involved in tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) receptor-mediated signal transduction. The FADD-caspase signaling pathway, which has been reported to be mostly related to apoptosis, was identified as being essential for DR4 or DR5 overexpression-mediated NF-κB activation and cytokine secretion and crosstalks with the TRADD-TRAF2-NIK-IKKα/β signaling cascade. Furthermore, a DR5 agonistic antibody (AD5-10) triggered the inflammatory cytokine release. These data, together with previous reports, provide strong evidence that TRAIL and TRAIL receptors play an important role in inflammation.

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“…The pivotal role of TRAIL in tumor defense is underlined by the observation that TRAIL-deficient mice are more susceptible to chemically induced as well as spontaneous tumors. [11][12][13] TRAIL-R1/2 expression in healthy cells, including hepatocytes and quiescent stellate cells, is absent or relatively low and often cytoplasmic, instead of membrane bound. [14][15][16] In contrast, in numerous cancers, including HCC, TRAIL-R1/2 protein expression is highly up-regulated.…”

mentioning

confidence: 99%

Increased apoptosis induction in hepatocellular carcinoma by a novel tumor-targeted TRAIL fusion protein combined with bortezomib

et al. 2013

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As the result of an increasing incidence and a prevalent therapy resistance of hepatocellular carcinoma (HCC), there is a strong need for novel strategies to enhance treatment responses in HCC. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) has been proposed as a promising anticancer drug because it can selectively induce apoptosis in cancer cells, but not in healthy cells. Nevertheless, most tumor cells show TRAIL resistance, emphasizing the requirement for apoptosis-sensitizing agents and TRAIL molecules with improved tumor specificity. In this study, we employed a recombinant TRAIL molecule, in which three TRAIL protomers were expressed as a single polypeptide chain (scTRAIL), and a novel TRAIL variant, in which scTRAIL was additionally fused to an antibody fragment recognizing epidermal growth factor receptor (EGFR) to improve its HCC-targeting properties. We analyzed the proapoptotic effects of both TRAIL versions in combination with the proteasome inhibitor bortezomib (BZB) in hepatoma cells and primary human hepatocytes as well as in intact explants from HCC and healthy liver tissue. We demonstrate that EGFR-targeted TRAIL in combination with BZB induced significantly higher caspase activation and cell death in hepatoma cells, but not in primary hepatocytes. Importantly, when incubated with fresh liver explants, the combination of EGFR-targeted TRAIL and BZB displayed selective cytotoxicity for HCC, but not for tumor-free liver tissue, which could even be verified in liver explants from the same individuals. Unlike nontargeted TRAIL, EGFR-targeted TRAIL combined with BZB exerted no toxicity in liver tissues from nonalcoholic fatty liver disease patients. Conclusion: EGFRtargeted TRAIL reveals increased antitumor activity toward HCC without inducing toxicity to tumor-free liver tissue and might therefore represent a promising novel strategy for HCC treatment. (HEPATOLOGY 2013;57:625-636) H epatocellular carcinoma (HCC) is a global health problem with increasing incidence. 1 In western countries, less than 50% of patients are eligible for potential curative treatment, including resection, transplantation, or local ablation. The limited therapeutic options and its resistance to systemic chemotherapy have triggered the search for moleculartargeted therapies for liver cancer. There is evidence of aberrant activation of several signaling cascades, such as the epidermal growth factor receptor (EGFR)/

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Cutting Edge: TRAIL Deficiency Accelerates Hematological Malignancies

Cited by 146 publications

References 24 publications

Antibodies targeted to TRAIL receptor-2 and ErbB-2 synergize in vivo and induce an antitumor immune response

Antibodies targeted to TRAIL receptor-2 and ErbB-2 synergize in vivo and induce an antitumor immune response

TRAIL receptor mediates inflammatory cytokine release in an NF-κB-dependent manner

Increased apoptosis induction in hepatocellular carcinoma by a novel tumor-targeted TRAIL fusion protein combined with bortezomib

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