Characterization of the immune microenvironment of diffuse intrinsic pontine glioma: implications for development of immunotherapy

Lieberman, Nicole A P; DeGolier, Kole; Kovar, Heather M; Davis, Amira; Hoglund, Virginia; Stevens, Jeffrey C.; Winter, Conrad; Deutsch, Gail H.; Furlan, Scott N.; Vitanza, Nicholas A.; Leary, Sarah; Crane, Courtney A.

doi:10.1093/neuonc/noy145

Cited by 135 publications

(151 citation statements)

References 39 publications

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“…In line with these findings, Lieberman et al show that in contrast to pediatric high-grade and low-grade glioma, DIPG tissue does not show enhanced T cell infiltration compared to adjacent non-tumor tissue. In addition, no increase in chemokines and inflammatory cytokines was observed (106). Collectively, these findings demonstrate minimal immune activation in the DIPG microenvironment in contrast to other types of brain tumors.…”

Section: Dipg Displays a Unique Immune Environment With Minimal Immunmentioning

confidence: 58%

Invaders Exposed: Understanding and Targeting Tumor Cell Invasion in Diffuse Intrinsic Pontine Glioma

et al. 2020

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Diffuse Intrinsic Pontine Glioma (DIPG) is a rare, highly aggressive pediatric brain tumor that originates in the pons. DIPG is untreatable and universally fatal, with a median life expectancy of less than a year. Resection is not an option, due to the anatomical location of the tumor, radiotherapy has limited effect and no chemotherapeutic or targeted treatment approach has proven to be successful. This poor prognosis is partly attributed to the tumor's highly infiltrative diffuse and invasive spread. Thus, targeting the invasive behavior of DIPG has the potential to be of therapeutic value. In order to target DIPG invasion successfully, detailed mechanistic knowledge on the underlying drivers is required. Here, we review both DIPG tumor cell's intrinsic molecular processes and extrinsic environmental factors contributing to DIPG invasion. Importantly, DIPG represents a heterogenous disease and through advances in whole-genome sequencing, different subtypes of disease based on underlying driver mutations are now being recognized. Recent evidence also demonstrates intra-tumor heterogeneity in terms of invasiveness and implies that highly infiltrative tumor subclones can enhance the migratory behavior of neighboring cells. This might partially be mediated by "tumor microtubes," long membranous extensions through which tumor cells connect and communicate, as well as through the secretion of extracellular vesicles. Some of the described processes involved in invasion are already being targeted in clinical trials. However, more research into the mechanisms of DIPG invasion is urgently needed and might result in the development of an effective therapy for children suffering from this devastating disease. We discuss the implications of newly discovered invasive mechanisms for therapeutic targeting and the challenges therapy development face in light of disease in the developing brain.

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Section: Dipg Displays a Unique Immune Environment With Minimal Immunmentioning

confidence: 58%

Invaders Exposed: Understanding and Targeting Tumor Cell Invasion in Diffuse Intrinsic Pontine Glioma

et al. 2020

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“…Glioblastoma (GBM) is the most frequent and the highest malignant glioma (grade IV), it usually causes significant mortality and morbidity, and it has a 5‐year overall survival (OS) of no > 5% . In the past few decades, the treatment of glioma has made great progress and development, including surgical resection, radiotherapy, chemotherapy, immunotherapy, and molecular targeted therapy . However, the prognosis of glioma remains poor, especially for GBM.…”

mentioning

confidence: 99%

Prognostic Significance of Preoperative Systemic Cellular Inflammatory Markers in Gliomas: A Systematic Review and Meta‐Analysis

Wang¹,

Kang

Lin

et al. 2019

Clinical Translational Sci

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Glioma is the most common malignant brain tumor and has high lethality. This tumor generated a robust inflammatory response that results in the deterioration of the disease. However, the prognostic role of systemic cellular inflammatory indicators in gliomas remains controversial. This meta‐analysis aimed to assess the prognostic significance of preoperative neutrophil/lymphocyte ratio (NLR), platelet/lymphocyte ratio (PLR), lymphocyte/monocyte ratio (LMR), red cell distribution width (RDW), and prognostic nutritional index (PNI) in patients with gliomas. Databases of PubMed, EMBASE, Web of Science, and The Cochrane Library were systematically searched for all studies published up to January 2019. Study screening and data extraction followed established Preferred Reporting Items for Systematic Reviews and Meta‐Analyses guidelines. The Newcastle–Ottawa Scale was used to assess the quality of studies. Eighteen studies containing 3,261 patients were included. The analyses showed an increased NLR or RDW was found to be an independent predictor of worse survival in patients with gliomas (hazard ratio (HR): 1.38; 95% confidence interval (CI): 1.09–1.74; P = 0.008; and HR: 1.40; 95% CI: 1.13–1.74; P = 0.002, respectively). Furthermore, a higher PNI indicates a better overall survival (OS; HR: 0.57; 95% CI: 0.42–0.77; P = 0.0002). For the evaluation of PLR and LMR, none of these variables correlated with OS (P = 0.91 and P = 0.21, respectively). Our meta‐analysis indicates the NLR, RDW, and PNI rather than PLR and LMR are the independent index for predicting the OS of gliomas. Pre‐operative NLR, RDW, and PNI can help to evaluate disease progression, optimize treatment, and follow‐up in patients with gliomas.

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“…GBM tumors establish an immunosuppressive environment by the release of immunosuppressive cytokines, such as TGF-β and IL-10, by the recruitment or induction of immunosuppressive cells, such as regulatory T cells, myeloid-derived suppressor cells, or tumor associated macrophages, and by the expression of immune checkpoint receptor ligands (47)(48)(49)(50)(51)(52)(53). In comparison to adult GBM, initial studies of the tumor microenvironment in DIPG have found that there is a low number of immune infiltrates in human DIPG tumors and that they do not express inflammatory cytokines and chemokines (54,55). These data provide support for the use of an immune modulatory therapeutic strategy to enhance the recruitment of immune cells into the tumor, with the aim of mounting an effective anti-DIPG immune response.…”

Section: Discussionmentioning

confidence: 99%

Therapeutic efficacy of an immune stimulatory gene therapy strategy in a mouse model of high grade brainstem glioma

Mendez

Kadiyala

Núñez

et al. 2019

Preprint

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The therapeutic efficacy of anti-DIPG immune responses is limited due to a low number of immune cells in the tumor microenvironment. We have uncovered a novel treatment strategy that utilizes adenoviral delivery of therapeutic genes, thymidine kinase (TK) and fms tyrosine kinase 3 ligand (Flt3L) into the tumor, eliciting a reprograming of the host's own immune system to recognize and kill tumor cells. We demonstrate that TK/Flt3L therapy generates an effective antitumor response and can be safely delivered into the brainstem. This treatment approach could provide a novel translational approach towards potentiating an anti-DIPG immune response to overcome the current limitations in the treatment of patients with DIPG. AbstractPurpose: Diffuse intrinsic pontine glioma (DIPG) bears a dismal prognosis. A genetically engineered brainstem glioma model harboring the recurrent DIPG mutation, ACVR1-G328V (mACVR1), was developed for testing an immune-stimulatory gene therapy. Experimental Design:We utilized the Sleeping Beauty transposase system to generate an endogenous mouse model of mACVR1 brainstem glioma. Histology was used to characterize and validate the model. We performed RNAseq analysis on neurospheres (NS) harboring mACVR1. mACVR1 NS were implanted into the pons of immune competent mice to test the therapeutic efficacy and toxicity of immune stimulatory gene therapy using adenoviruses expressing thymidine kinase (TK) and fms-like tyrosine kinase 3 ligand (Flt3L). mACVR1 NS expressing the surrogate tumor antigen ovalbumin were generated to investigate if TK/Flt3L treatment induces the recruitment of tumor-antigen specific T cells.Results: Histological analysis of mACVR1 tumors indicates that they are localized in the brainstem and have increased downstream signaling of bone morphogenetic pathway as demonstrated by increased phospho-smad1/5 and Id1 levels. Transcriptome analysis of mACVR1 NS identified an increase in the transforming growth factor beta (TGF-β) signaling pathway and the regulation of cell differentiation. Adenoviral delivery of TK/Flt3L in mice bearing brainstem gliomas resulted in anti-tumor immunity, recruitment of anti-tumor specific T cells and increased median survival. Conclusions:This study provides insights into the phenotype and function of the tumor immune microenvironment in a mouse model of brainstem glioma harboring mACVR1. Immune stimulatory gene therapy targeting the hosts' anti-tumor immune response inhibits tumor progression and increases median survival of mice bearing mACVR1 tumors.

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Characterization of the immune microenvironment of diffuse intrinsic pontine glioma: implications for development of immunotherapy

Abstract: DIPG tumors have neither a highly immunosuppressive nor inflammatory microenvironment. Therefore, major considerations for the development of immunotherapy will be the recruitment, activation, and retention of tumor-specific effector immune cells.

Cited by 135 publications

References 39 publications

Invaders Exposed: Understanding and Targeting Tumor Cell Invasion in Diffuse Intrinsic Pontine Glioma

Invaders Exposed: Understanding and Targeting Tumor Cell Invasion in Diffuse Intrinsic Pontine Glioma

Prognostic Significance of Preoperative Systemic Cellular Inflammatory Markers in Gliomas: A Systematic Review and Meta‐Analysis

Therapeutic efficacy of an immune stimulatory gene therapy strategy in a mouse model of high grade brainstem glioma

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