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TRAIL-receptor 1 IgM antibodies strongly induce apoptosis in human cancer cells in vitro and in vivo.

ABSTRACT: Agonistic tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL)-receptor-specific antibodies are attractive antitumor therapeutics. Recently, our group has generated several human monoclonal antibodies (mAbs) to TRAIL-receptor-1 (TRAIL-R1) (TR1-IgGs) using ISAAC technology. However, these TR1-IgGs did not demonstrate ideal apoptosis-inducing capacity in the absence of additional antibodies. To overcome this limitation, we class-switched the TR1-IgGs to TRAIL-R1 IgM antibodies (TR1-IgMs); TR1-IgMs might possess high valency and facilitate the crosslinking of the cell surface receptors. We showed that the TR1-IgMs bound TRAIL-R1, activated the caspase signal, and induced strong apoptosis (100-fold higher compared with the IgG form in one case) in human tumor cell lines without any additional crosslinking in vitro. We further demonstrated that these TR1-IgMs dramatically inhibited tumor growth in a xenograft model through the caspase activation cascade. These data suggest that TR1-IgMs may become potential immunotherapeutic agents for cancer therapy.

SUBMITTER: Piao X

PROVIDER: S-EPMC4910746 | biostudies-literature | 2016 May

REPOSITORIES: biostudies-literature

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TRAIL-receptor 1 IgM antibodies strongly induce apoptosis in human cancer cells in vitro and in vivo.

Piao Xiuhong X Ozawa Tatsuhiko T Hamana Hiroshi H Shitaoka Kiyomi K Jin Aishun A Kishi Hiroyuki H Muraguchi Atsushi A

Oncoimmunology 20160504 5

Agonistic tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL)-receptor-specific antibodies are attractive antitumor therapeutics. Recently, our group has generated several human monoclonal antibodies (mAbs) to TRAIL-receptor-1 (TRAIL-R1) (TR1-IgGs) using ISAAC technology. However, these TR1-IgGs did not demonstrate ideal apoptosis-inducing capacity in the absence of additional antibodies. To overcome this limitation, we class-switched the TR1-IgGs to TRAIL-R1 IgM antibodies (TR ...[more]

PMID: 27467950

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Project description:BACKGROUND:Esophageal cancer is one of the most common malignant tumors in the world. With currently available therapies, only 20% ~?30% patients can survive this disease for more than 5?years. TRAIL, a natural ligand for death receptors that can induce the apoptosis of cancer cells, has been explored as a therapeutic agent for cancers, but it has been reported that many cancer cells are resistant to TRAIL, limiting the potential clinical use of TRAIL as a cancer therapy. Meanwhile, Periplocin (CPP), a natural compound from dry root of Periploca sepium Bge, has been studied for its anti-cancer activity in a variety of cancers. It is not clear whether CPP and TRAIL can have activity on esophageal squamous cell carcinoma (ESCC) cells, or whether the combination of these two agents can have synergistic activity. METHODS:We used MTS assay, flow cytometry and TUNEL assay to detect the effects of CPP alone or in combination with TRAIL on ESCC cells. The mechanism of CPP enhances the activity of TRAIL was analyzed by western blot, dual luciferase reporter gene assay and chromatin immunoprecipitation (ChIP) assay. The anti-tumor effects and the potential toxic side effects of CPP alone or in combination with TRAIL were also evaluated in vivo. RESULTS:In our studies, we found that CPP alone or in combination with TRAIL could inhibit the proliferation of ESCC cells and induce apoptosis, and we certificated that combination of two agents exert synergized functions. For the first time, we identified FoxP3 as a key transcriptional repressor for both DR4 and DR5. By down-regulating FoxP3, CPP increases the expression of DR4/DR5 and renders ESCC cells much more sensitive to TRAIL. We also showed that CPP reduced the expression of Survivin by inhibiting the activity of Wnt/?-catenin pathway. All these contributed to synergistic activity of CPP and TRAIL on ESCC cells in vitro and in vivo. CONCLUSION:Our data suggest that CPP and TRAIL could be further explored as potential therapeutic approach for esophageal cancer.

Project description:The maintenance of B cell homeostasis requires a tight control of B cell generation, survival, activation, and maturation. In lymphocytes upon activation, increased sensitivity to apoptotic signals helps controlling differentiation and proliferation. The death receptor Fas is important in this context because genetic Fas mutations in humans lead to an autoimmune lymphoproliferative syndrome that is similar to lymphoproliferation observed in Fas-deficient mice. In contrast, the physiological role of TNF-related apoptosis-inducing ligand receptors (TRAIL-Rs) in humans has been poorly studied so far. Indeed, most studies have focused on tumor cell lines and on mouse models whose results are difficult to transpose to primary human B cells. In the present work, the expression of apoptosis-inducing TRAIL-R1 and TRAIL-R2 and of the decoy receptors TRAIL-R3 and TRAIL-R4 was systematically studied in all developmental stages of peripheral B cells isolated from the blood and secondary lymphoid organs. Expression of TRAIL-Rs is modulated along development, with highest levels observed in germinal center B cells. In addition, T-dependent and T-independent signals elicited induction of TRAIL-Rs with distinct kinetics, which differed among B cell subpopulations: switched memory cells rapidly upregulated TRAIL-R1 and -2 upon activation while naïve B cells only reached similar expression levels at later time points in culture. Increased expression of TRAIL-R1 and -2 coincided with a caspase-3-dependent sensitivity to TRAIL-induced apoptosis in activated B cells but not in freshly isolated resting B cells. Finally, both TRAIL-R1 and TRAIL-R2 could signal actively and both contributed to TRAIL-induced apoptosis. In conclusion, this study provides a systematic analysis of the expression of TRAIL-Rs in human primary B cells and of their capacity to signal and induce apoptosis. This dataset forms a basis to further study and understand the dysregulation of TRAIL-Rs and TRAIL expression observed in autoimmune diseases. Additionally, it will be important to foresee potential bystander immunomodulation when TRAIL-R agonists are used in cancer treatment.

Dataset Information

TRAIL-receptor 1 IgM antibodies strongly induce apoptosis in human cancer cells in vitro and in vivo.

Publications

TRAIL-receptor 1 IgM antibodies strongly induce apoptosis in human cancer cells in vitro and in vivo.

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