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Title :OX40 ligand expressed in glioblastoma modulates adaptive immunity depending on the microenvironment : a clue for successful immunotherapy
Authors :Shibahara, Ichiyo
Saito, Ryuta
Zhang, Rong
Chonan, Masashi
Shoji, Takuhiro
Kanamori, Masayuki
Sonoda, Yukihiko
Kumabe, Toshihiro
Kanehira, Masahiko
Kikuchi, Toshiaki
So, Takanori
Watanebe, Takashi
Takahashi, Hiroaki
Iwabuchi, Erina
Tanaka, Yuetsu
Shibahara, Yukiko
Sasano, Hironobu
Ishii, Naoto
Tominaga, Teiji
Issue Date :15-Feb-2015
Abstract :Background: Glioblastoma is the most malignant human brain tumor and has a dismal prognosis; however, some patients show long-term survival. The interaction between the costimulatory molecule OX40 and its ligand OX40L generates key signals for T-cell activation. The augmentation of this interaction enhances antitumor immunity. In this present study, we explored whether OX40 signaling is responsible for antitumor adaptive immunity against glioblastoma and also established therapeutic antiglioma vaccination therapy. Methods: Tumor specimens were obtained from patients with primary glioblastoma (n = 110) and grade III glioma (n = 34). Quantitative polymerase chain reaction (PCR), flow cytometry, and immunohistochemistry were used to analyze OX40L expression in human glioblastoma specimens. Functional consequences of OX40 signaling were studied using glioblastoma cell lines, mouse models of glioma, and T cells isolated from human subjects and mice. Cytokine production assay with mouse regulatory T cells was conducted under hypoxic conditions (1.5% O_2). Results: OX40L mRNA was expressed in glioblastoma specimens and higher levels were associated with prolonged progression-free survival of patients with glioblastoma, who had undergone gross total resection. In this regard, OX40L protein was expressed in A172 human glioblastoma cells and its expression was induced under hypoxia, which mimics the microenvironment of glioblastoma. Notably, human CD4 T cells were activated when cocultured in anti-CD3-coated plates with A172 cells expressing OX40L, as judged by the increased production of interferon-γ. To confirm the survival advantage of OX40L expression, we then used mouse glioma models. Mice bearing glioma cells forced to express OX40L did not die during the observed period after intracranial transplantation, whereas all mice bearing glioma cells lacking OX40L died. Such a survival benefit of OX40L was not detected in nude mice with an impaired immune system. Moreover, compared with systemic intraperitoneal injection, the subcutaneous injection of the OX40 agonist antibody together with glioma cell lysates elicited stronger antitumor immunity and prolonged the survival of mice bearing glioma or glioma-initiating cell-like cells. Finally, OX40 triggering activated regulatory T cells cultured under hypoxia led to the induction of the immunosuppressive cytokine IL10. Conclusion: Glioblastoma directs immunostimulation or immunosuppression through OX40 signaling, depending on its microenvironment.
URL :https://doi.org/10.1186/s12943-015-0307-3
Type Local :雑誌掲載論文
ISSN :1476-4598
Publisher :BioMed Central
URI :http://hdl.handle.net/20.500.12000/45952
Citation :Molecular Cancer Vol.14
Appears in Collections:Peer-reviewed Journal Articles (Faculty of Medicine)

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