Decoy receptors block TRAIL sensitivity at a supracellular level: the role of stromal cells in controlling tumour TRAIL sensitivity

O'Leary, Lynda; Sloot, Almer M. van der; Reis, Carlos R.; Deegan, Shane; Ryan, Aideen E.; Dhami, Sukhraj Pal Singh; Murillo, Laura S.; Cool, Robbert H.; Sampaio, Pedro Corrêa de; Thompson, Kerry; Murphy, Gillian; Quax, Wim J.; Serrano, Luís; Samali, Afshin; Szegezdi, Éva

doi:10.1038/onc.2015.180

Cited by 62 publications

(55 citation statements)

References 42 publications

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“…The structural optimization described here could potentially also be applied for death receptor (DR4/DR5) selective TRAIL variants in order to avoid competition with decoy receptors that could affect the efficacy of TRAIL-based therapies. 43 A possible approach combining such receptor-selective mutations with our refined concept for single-chain TRAIL described here could lead to the development of novel TRAIL-based therapies in oncology.…”

Section: Discussionmentioning

confidence: 99%

An optimized antibody-single-chain TRAIL fusion protein for cancer therapy

Siegemund

Seifert

Zarani³

et al. 2016

mAbs

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Fusion proteins combining oligomeric assemblies of a genetically obtained single-chain (sc) variant of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) with antibodies directed against tumorassociated antigens represent a promising strategy to overcome the limited therapeutic activity of conventional soluble TRAIL. To further improve the scTRAIL module in order to obtain a robust, thermostable molecule of high activity, we performed a comprehensive analysis of the minimal TNF homology domain (THD) and optimized linkers between the 3 TRAIL subunits constituting a scTRAIL. Through a stepwise mutagenesis of the N-and C-terminal region and the joining linker sequences, we generated bioactive scTRAIL molecules comprising a covalent linkage of the C-terminal Val280 and the Nterminal position 122 by only 2 amino acid residues in combination with conservative exchanges at positions 122 and 279. The increased thermal stability and solubility of such optimized scTRAIL molecules translated into increased bioactivity in the diabody-scTRAIL (Db-scTRAIL) format, exemplified here for an epidermal growth factor receptor-specific Db-scTRAIL. Additional modifications within the diabody linkers resulted in a fusion protein exerting high, target-dependent apoptosis induction in tumor cell lines in vitro and potent antitumor activity in vivo. Our results illustrate that protein engineering of scTRAIL and associated peptide linkers provides a promising strategy to develop antibody-scTRAIL fusion proteins as effective antitumor therapeutics.

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Section: Discussionmentioning

confidence: 99%

An optimized antibody-single-chain TRAIL fusion protein for cancer therapy

Siegemund

Seifert

Zarani³

et al. 2016

mAbs

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“…However, TRAIL was engineered in order to escape from binding to DcRs, which were found to still exert trans-cellular regulation originating from stromal cells and affect tumor cells. Therefore, it is important to target these decoy receptors selectively to gain maximum efficacy [106]. Another recent study showed that DR4 and DR5 were upregulated while DcR1 and DcR2 downregulated in colon cancer cells after their treatment with a non-steroidal anti-inflammatory drug.…”

Section: Fas Cell Surface Death Receptor and Fas Ligandmentioning

confidence: 99%

Major apoptotic mechanisms and genes involved in apoptosis

et al. 2016

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As much as the cellular viability is important for the living organisms, the elimination of unnecessary or damaged cells has the opposite necessity for the maintenance of homeostasis in tissues, organs and the whole organism. Apoptosis, a type of cell death mechanism, is controlled by the interactions between several molecules and responsible for the elimination of unwanted cells from the body. Apoptosis can be triggered by intrinsically or extrinsically through death signals from the outside of the cell. Any abnormality in apoptosis process can cause various types of diseases from cancer to auto-immune diseases. Different gene families such as caspases, inhibitor of apoptosis proteins, B cell lymphoma (Bcl)-2 family of genes, tumor necrosis factor (TNF) receptor gene superfamily, or p53 gene are involved and/or collaborate in the process of apoptosis. In this review, we discuss the basic features of apoptosis and have focused on the gene families playing critical roles, activation/inactivation mechanisms, upstream/downstream effectors, and signaling pathways in apoptosis on the basis of cancer studies. In addition, novel apoptotic players such as miRNAs and sphingolipid family members in various kind of cancer are discussed.

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“…Ubiquitous DcR1 (but not DcR2) expression has also been reported in the tumor-surrounding stroma of various cancers including breast, liver, pancreatic, ovarian, and prostrate (101). While deficient mTRAIL-R expression in mice promotes metastasis (102), it is not known if DcR1 and/or DcR2 can lend similar properties to tumors.…”

Section: Death Receptor Signaling In Tumor Immune Escapementioning

confidence: 99%

“…The importance of receptor selectivity has been recognized for some time and selective agonists against the TRAIL DRs either in form of agonistic antibodies or engineered ligand variants have been developed (101, 152). The ability of these agonists to fully replicate the receptor-activation mechanisms of the membrane-bound native ligand, however, has not been fully elucidated yet.…”

Section: Targeting Death Receptor Signaling For Anticancer Therapymentioning

confidence: 99%

The Janus Face of Death Receptor Signaling during Tumor Immunoediting

et al. 2016

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Cancer immune surveillance is essential for the inhibition of carcinogenesis. Malignantly transformed cells can be recognized by both the innate and adaptive immune systems through different mechanisms. Immune effector cells induce extrinsic cell death in the identified tumor cells by expressing death ligand cytokines of the tumor necrosis factor ligand family. However, some tumor cells can escape immune elimination and progress. Acquisition of resistance to the death ligand-induced apoptotic pathway can be obtained through cleavage of effector cell expressed death ligands into a poorly active form, mutations or silencing of the death receptors, or overexpression of decoy receptors and pro-survival proteins. Although the immune system is highly effective in the elimination of malignantly transformed cells, abnormal/dysfunctional death ligand signaling curbs its cytotoxicity. Moreover, DRs can also transmit pro-survival and pro-migratory signals. Consequently, dysfunctional death receptor-mediated apoptosis/necroptosis signaling does not only give a passive resistance against cell death but actively drives tumor cell motility, invasion, and contributes to consequent metastasis. This dual contribution of the death receptor signaling in both the early, elimination phase, and then in the late, escape phase of the tumor immunoediting process is discussed in this review. Death receptor agonists still hold potential for cancer therapy since they can execute the tumor-eliminating immune effector function even in the absence of activation of the immune system against the tumor. The opportunities and challenges of developing death receptor agonists into effective cancer therapeutics are also discussed.

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Decoy receptors block TRAIL sensitivity at a supracellular level: the role of stromal cells in controlling tumour TRAIL sensitivity

Cited by 62 publications

References 42 publications

An optimized antibody-single-chain TRAIL fusion protein for cancer therapy

An optimized antibody-single-chain TRAIL fusion protein for cancer therapy

Major apoptotic mechanisms and genes involved in apoptosis

The Janus Face of Death Receptor Signaling during Tumor Immunoediting

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