TY - JOUR
T1 - OX40 ligand expressed in glioblastoma modulates adaptive immunity depending on the microenvironment
T2 - A clue for successful immunotherapy
AU - Shibahara, Ichiyo
AU - Saito, Ryuta
AU - Zhang, Rong
AU - Chonan, Masashi
AU - Shoji, Takuhiro
AU - Kanamori, Masayuki
AU - Sonoda, Yukihiko
AU - Kumabe, Toshihiro
AU - Kanehira, Masahiko
AU - Kikuchi, Toshiaki
AU - So, Takanori
AU - Watanabe, Takashi
AU - Takahashi, Hiroaki
AU - Iwabuchi, Erina
AU - Tanaka, Yuetsu
AU - Shibahara, Yukiko
AU - Sasano, Hironobu
AU - Ishii, Naoto
AU - Tominaga, Teiji
N1 - Publisher Copyright:
© Shibahara et al.
Copyright:
Copyright 2015 Elsevier B.V., All rights reserved.
PY - 2015/2/15
Y1 - 2015/2/15
N2 - 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% O2). 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.
AB - 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% O2). 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.
KW - Glioblastoma
KW - Hypoxia
KW - Immunotherapy
KW - OX40
KW - OX40 ligand
KW - Regulatory T cell
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UR - http://www.scopus.com/inward/citedby.url?scp=84925448470&partnerID=8YFLogxK
U2 - 10.1186/s12943-015-0307-3
DO - 10.1186/s12943-015-0307-3
M3 - Article
C2 - 25744203
AN - SCOPUS:84925448470
VL - 14
JO - Molecular Cancer
JF - Molecular Cancer
SN - 1476-4598
IS - 1
M1 - 41
ER -