OX40 ligand expressed in glioblastoma modulates adaptive immunity depending on the microenvironment: a clue for successful immunotherapy

Abstract

BackgroundGlioblastoma 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.MethodsTumor 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).ResultsOX40L 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.ConclusionGlioblastoma directs immunostimulation or immunosuppression through OX40 signaling, depending on its microenvironment.Electronic supplementary materialThe online version of this article (doi:10.1186/s12943-015-0307-3) contains supplementary material, which is available to authorized users.

Systemic T Cells Immunosuppression of Glioma Stem Cell-Derived Exosomes Is Mediated by Monocytic Myeloid-Derived Suppressor Cells

“…However, it has been reported that glioma cell lines-derived exosomes lack antigen-presentation and the surface co-modulatory machinery CD80 and CD86 [34] able to cross-react with CD28. It is probable that the presence of other costimulatory molecules such as CD275 (Inducible T-cell co-stimulator ligand, ICOSL) or CD252 (OX40 ligand), which are expressed on glioma cells [38,39], could account for the result that we have observed. A new set of experiments would be required to investigate the implications of this finding, even if this lies outside of the objectives of this work.…”

Immunoregulatory functions of VISTA

“…One study tested an allogeneic cell‐based vaccine that secreted Fc‐OX40L, Fc‐ICOSL, or Fc‐4‐1BBL versus systemic agonist antibody and found that OX40 was the most effectively targeted pathway . In murine tumor models, OX40 agonist antibody has enhanced survival as a monotherapy or combined with CTLA‐4 blockade . Treatment expanded Tbet hi Eomes hi Granzyme B + CD8 T cells and both Th1 and Th2 CD4 T cells .…”

OX40 triggering concomitant to IL12-engineered cell vaccine hampers the immunoprevention of HER2/neu-driven mammary carcinogenesis

“…Increased expression of IL10 and GM-CSF was reported by OX40 triggering in some studies. 21 , 24 It is worth noting that IL10, which is generally considered as a suppressor cytokine, also has antitumor activities. 25-27 …”