CD40/CD40L expression correlates with the survival of patients with glioblastomas and an augmentation in CD40 signaling enhances the efficacy of vaccinations against glioma models

Chonan, Masashi; Saito, Ryuta; Shoji, Taku; Shibahara, Ichiyo; Kanamori, Masayuki; Sonoda, Yukihiko; Watanabe, Mika; Kikuchi, Toshiaki; Ishii, Naoto; Tominaga, Teiji

doi:10.1093/neuonc/nov090

Cited by 53 publications

(51 citation statements)

References 24 publications

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“…In contrast, CD40 expression was not observed, either on tumor or on tumor-associated microglia/macrophage (TAM) cells. Interestingly, CD40L expression in glioblastoma cells was first reported in 2015 and found to be a positive prognostic factor, while co-expression of both CD40 and CD40L in glioblastoma cells correlated with negative prognosis [ 46 ]. It is noteworthy that in the ParvOryx01 study, CD40 + cells with a non-macrophage phenotype were observed in the tumor blood vessel lumen in patients who received H-1PV by intravenous infusion ( Figure 1 ).…”

Section: Immunotherapeutic Potential Of H-1pv In Glioblastoma Patimentioning

confidence: 99%

Immunotherapeutic Potential of Oncolytic H-1 Parvovirus: Hints of Glioblastoma Microenvironment Conversion towards Immunogenicity

Angelova

Barf

Geletneky

et al. 2017

Viruses

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Glioblastoma, one of the most aggressive primary brain tumors, is characterized by highly immunosuppressive microenvironment. This contributes to glioblastoma resistance to standard treatment modalities and allows tumor growth and recurrence. Several immune-targeted approaches have been recently developed and are currently under preclinical and clinical investigation. Oncolytic viruses, including the autonomous protoparvovirus H-1 (H-1PV), show great promise as novel immunotherapeutic tools. In a first phase I/IIa clinical trial (ParvOryx01), H-1PV was safe and well tolerated when locally or systemically administered to recurrent glioblastoma patients. The virus was able to cross the blood–brain (tumor) barrier after intravenous infusion. Importantly, H-1PV treatment of glioblastoma patients was associated with immunogenic changes in the tumor microenvironment. Tumor infiltration with activated cytotoxic T cells, induction of cathepsin B and inducible nitric oxide (NO) synthase (iNOS) expression in tumor-associated microglia/macrophages (TAM), and accumulation of activated TAM in cluster of differentiation (CD) 40 ligand (CD40L)-positive glioblastoma regions was detected. These are the first-in-human observations of H-1PV capacity to switch the immunosuppressed tumor microenvironment towards immunogenicity. Based on this pilot study, we present a tentative model of H-1PV-mediated modulation of glioblastoma microenvironment and propose a combinatorial therapeutic approach taking advantage of H-1PV-induced microglia/macrophage activation for further (pre)clinical testing.

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Section: Immunotherapeutic Potential Of H-1pv In Glioblastoma Patimentioning

confidence: 99%

Immunotherapeutic Potential of Oncolytic H-1 Parvovirus: Hints of Glioblastoma Microenvironment Conversion towards Immunogenicity

Angelova

Barf

Geletneky

et al. 2017

Viruses

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“…To strengthen this conclusion, we also observed neutrophilic influx, ROS generation, and cell survival after intraperitoneal injection of 0.25 mg OX86 (22) or rat IgG into Rag2/Il2rg -/mice at the beginning of reperfusion. Consistent with the results of experiments in vitro, OX86 injection significantly increased neutrophil infiltration and ROS generation in vivo, while enhancing cell survival ( Figure 6, H-J).…”

Section: Hiri Upregulates Ox40 Expression In Neutrophilsmentioning

confidence: 80%

OX40 expression in neutrophils promotes hepatic ischemia/reperfusion injury

Jin¹,

Zhang²,

Sun³

et al. 2019

JCI Insight

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“…CD40 is a cell-surface member of the tumor necrosis factor (TNF) receptor superfamily that is most prominently expressed on dendritic cells, B cells, and myeloid cells and leads to dendritic cell activation, thus playing a critical role in regulating T cell priming in tumors [40]. In GBM, CD40/CD40L mRNA expression has been associated with improved survival [41], and antitumor effects have been demonstrated with an anti-CD40 agonistic monoclonal antibody in mouse glioma models [42]. CD137, GITR, and OX40 are also members of the TNF receptor superfamily, and each are immune co-stimulatory receptors expressed on CD4+ and CD8+ T cells, as well as Tregs [43].…”

Section: Discussionmentioning

confidence: 99%

RNA-seq for identification of therapeutically targetable determinants of immune activation in human glioblastoma

et al. 2018

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Introduction: We sought to determine which therapeutically targetable immune checkpoints, costimulatory signals, and other tumor microenvironment (TME) factors are independently associated with immune cytolytic activity (CYT), a gene expression signature of activated effector T cells, in human glioblastoma (GBM). Methods: GlioVis was accessed for RNA-seq data from The Cancer Genome Atlas (TCGA). For subjects with treatment-naïve, primary GBM, we quantified mRNA expression of 28 therapeutically targetable TME factors. CYT (geometric mean of GZMA and PRF1 expression) was calculated for each tumor. Multiple linear regression was performed to determine the relationship between the dependent variable (CYT) and mRNA expression of each of the 28 factors. Variables associated with CYT in multivariate analysis were subsequently evaluated for this association in an independent cohort of newly diagnosed GBMs from the Chinese Glioma Cooperative Group (CGCG). Results: 109 TCGA tumors were analyzed. The final multiple linear regression model included the following variables, each positively associated with CYT except VEGF-A (negative association): CSF-1 (p=0.003), CD137 (p=0.042), VEGF-A (p<0.001), CTLA4 (p=0.028), CD40 (p=0.023), GITR (p=0.020), IL6 (p=0.02), and OX40 (p<0.001). In CGCG (n=52), each of these variables remained significantly associated with CYT in univariate analysis except for VEGF-A. In multivariate analysis, only CTLA4 and CD40 remained statistically significant. Conclusions: Using multivariate modeling of RNA-seq gene expression data, we identified therapeutically targetable TME factors that are independently associated with intratumoral cytolytic T-cell activity in human GBM. As a myriad of systemic immunotherapies are now available for investigation, our results could inform rational combinations for evaluation in GBM.

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CD40/CD40L expression correlates with the survival of patients with glioblastomas and an augmentation in CD40 signaling enhances the efficacy of vaccinations against glioma models

Abstract: The high expression of CD40/CD40L can be used as a biomarker for better prognoses in patients with gliomas. Immunotherapy using FGK45 significantly prolonged survival and represents a potential therapeutic strategy for gliomas including glioma-initiating cells.

Cited by 53 publications

References 24 publications

Immunotherapeutic Potential of Oncolytic H-1 Parvovirus: Hints of Glioblastoma Microenvironment Conversion towards Immunogenicity

Immunotherapeutic Potential of Oncolytic H-1 Parvovirus: Hints of Glioblastoma Microenvironment Conversion towards Immunogenicity

OX40 expression in neutrophils promotes hepatic ischemia/reperfusion injury

RNA-seq for identification of therapeutically targetable determinants of immune activation in human glioblastoma

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