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1.
Cell ; 184(5): 1281-1298.e26, 2021 03 04.
Article in English | MEDLINE | ID: mdl-33592174

ABSTRACT

T cells are critical effectors of cancer immunotherapies, but little is known about their gene expression programs in diffuse gliomas. Here, we leverage single-cell RNA sequencing (RNA-seq) to chart the gene expression and clonal landscape of tumor-infiltrating T cells across 31 patients with isocitrate dehydrogenase (IDH) wild-type glioblastoma and IDH mutant glioma. We identify potential effectors of anti-tumor immunity in subsets of T cells that co-express cytotoxic programs and several natural killer (NK) cell genes. Analysis of clonally expanded tumor-infiltrating T cells further identifies the NK gene KLRB1 (encoding CD161) as a candidate inhibitory receptor. Accordingly, genetic inactivation of KLRB1 or antibody-mediated CD161 blockade enhances T cell-mediated killing of glioma cells in vitro and their anti-tumor function in vivo. KLRB1 and its associated transcriptional program are also expressed by substantial T cell populations in other human cancers. Our work provides an atlas of T cells in gliomas and highlights CD161 and other NK cell receptors as immunotherapy targets.


Subject(s)
Glioma/immunology , NK Cell Lectin-Like Receptor Subfamily B/genetics , T-Lymphocytes/immunology , Animals , Antigens, Neoplasm , Disease Models, Animal , Gene Expression Profiling , Glioma/genetics , Killer Cells, Natural/immunology , Lectins, C-Type/genetics , Lymphocytes, Tumor-Infiltrating/immunology , Mice , Receptors, Cell Surface/genetics , Single-Cell Analysis , T-Lymphocyte Subsets/immunology , T-Lymphocytes/cytology , Tumor Escape
2.
Cell ; 178(4): 835-849.e21, 2019 08 08.
Article in English | MEDLINE | ID: mdl-31327527

ABSTRACT

Diverse genetic, epigenetic, and developmental programs drive glioblastoma, an incurable and poorly understood tumor, but their precise characterization remains challenging. Here, we use an integrative approach spanning single-cell RNA-sequencing of 28 tumors, bulk genetic and expression analysis of 401 specimens from the The Cancer Genome Atlas (TCGA), functional approaches, and single-cell lineage tracing to derive a unified model of cellular states and genetic diversity in glioblastoma. We find that malignant cells in glioblastoma exist in four main cellular states that recapitulate distinct neural cell types, are influenced by the tumor microenvironment, and exhibit plasticity. The relative frequency of cells in each state varies between glioblastoma samples and is influenced by copy number amplifications of the CDK4, EGFR, and PDGFRA loci and by mutations in the NF1 locus, which each favor a defined state. Our work provides a blueprint for glioblastoma, integrating the malignant cell programs, their plasticity, and their modulation by genetic drivers.


Subject(s)
Brain Neoplasms/genetics , Cell Plasticity/genetics , Glioblastoma/genetics , Adolescent , Aged , Animals , Brain Neoplasms/pathology , Cell Line, Tumor , Cell Lineage/genetics , Child , Cohort Studies , Disease Models, Animal , Female , Genetic Heterogeneity , Glioblastoma/pathology , Heterografts , Humans , Infant , Male , Mice , Mice, Inbred C57BL , Mice, Inbred NOD , Middle Aged , Mutation , RNA-Seq , Single-Cell Analysis/methods , Tumor Microenvironment/genetics
3.
Cell ; 157(3): 580-94, 2014 Apr 24.
Article in English | MEDLINE | ID: mdl-24726434

ABSTRACT

Developmental fate decisions are dictated by master transcription factors (TFs) that interact with cis-regulatory elements to direct transcriptional programs. Certain malignant tumors may also depend on cellular hierarchies reminiscent of normal development but superimposed on underlying genetic aberrations. In glioblastoma (GBM), a subset of stem-like tumor-propagating cells (TPCs) appears to drive tumor progression and underlie therapeutic resistance yet remain poorly understood. Here, we identify a core set of neurodevelopmental TFs (POU3F2, SOX2, SALL2, and OLIG2) essential for GBM propagation. These TFs coordinately bind and activate TPC-specific regulatory elements and are sufficient to fully reprogram differentiated GBM cells to "induced" TPCs, recapitulating the epigenetic landscape and phenotype of native TPCs. We reconstruct a network model that highlights critical interactions and identifies candidate therapeutic targets for eliminating TPCs. Our study establishes the epigenetic basis of a developmental hierarchy in GBM, provides detailed insight into underlying gene regulatory programs, and suggests attendant therapeutic strategies. PAPERCLIP:


Subject(s)
Brain Neoplasms/genetics , Brain Neoplasms/pathology , Glioblastoma/genetics , Glioblastoma/pathology , Neoplastic Stem Cells/pathology , Basic Helix-Loop-Helix Transcription Factors/metabolism , Brain Neoplasms/metabolism , Cell Differentiation , Cell Line, Tumor , Cells, Cultured , Co-Repressor Proteins/metabolism , Epigenesis, Genetic , Gene Expression Regulation, Neoplastic , Glioblastoma/metabolism , Humans , Neoplastic Stem Cells/metabolism , Nerve Tissue Proteins/metabolism , Oligodendrocyte Transcription Factor 2 , Regulatory Elements, Transcriptional , Transcription Factors/metabolism
4.
J Neurooncol ; 166(1): 59-71, 2024 Jan.
Article in English | MEDLINE | ID: mdl-38146046

ABSTRACT

PURPOSE: Atypical meningiomas could manifest early recurrence after surgery and even adjuvant radiotherapy. We aimed to construct a clinico-radiomics model to predict post-operative recurrence of atypical meningiomas based on clinicopathological and radiomics features. MATERIALS AND METHODS: The study cohort was comprised of 224 patients from two neurosurgical centers. 164 patients from center I were divided to the training cohort for model development and the testing cohort for internal validation. 60 patients from center II were used for external validation. Clinicopathological characteristics, radiological semantic, and radiomics features were collected. A radiomic signature was comprised of four radiomics features. A clinico-radiomics model combining the radiomics signature and clinical characteristics was constructed to predict the recurrence of atypical meningiomas. RESULTS: 1920 radiomics features were extracted from the T1 Contrast and T2-FLAIR sequences of patients in center I. The radiomics signature was able to differentiate post-operative patients into low-risk and high-risk groups based on tumor recurrence (P < 0.001). A clinic-radiomics model was established by combining age, extent of resection, Ki-67 index, surgical history and the radiomics signature for recurrence prediction in atypical meningiomas. The model achieved a good prediction performance with the integrated AUC of 0.858 (0.802-0.915), 0.781 (0.649-0.912) and 0.840 (0.747-0.933) in the training, internal validation and external validation cohort, respectively. CONCLUSIONS: The present study established a radiomics signature and a clinico-radiomics model with a favorable performance in predicting tumor recurrence for atypical meningiomas.


Subject(s)
Meningeal Neoplasms , Meningioma , Humans , Meningioma/diagnostic imaging , Meningioma/surgery , Neoplasm Recurrence, Local/diagnostic imaging , Neoplasm Recurrence, Local/surgery , Radiomics , Postoperative Period , Meningeal Neoplasms/diagnostic imaging , Meningeal Neoplasms/surgery , Retrospective Studies
5.
J Neurooncol ; 168(2): 355-365, 2024 Jun.
Article in English | MEDLINE | ID: mdl-38557927

ABSTRACT

PURPOSE: The proximate localization of MTAP, which encodes methylthioadenosine phosphorylase, and CDKN2A/B on Chromosome 9q21 has allowed the loss of MTAP expression as a surrogate for homozygous deletion of CDKN2A/B. This study aimed to determine whether MTAP status correlates with clinical outcomes and 11C-methionine uptake in astrocytomas with IDH mutations. METHODS: We conducted immunohistochemistry for MTAP in 30 patients with astrocytoma, IDH-mutant who underwent 11C-methionine positron emission tomography scans prior to surgical resection. The tumor-to-normal (T/N) ratio of 11C-methionine uptake was calculated using the mean standardized uptake value (SUV) for tumor and normal brain tissues. Cox regression analysis was used for multivariate survival analysis. RESULTS: Among IDH-mutant astrocytomas, 26.7% (8/30) exhibited the loss of cytoplasmic MTAP expression, whereas 73.3% (22/30) tumors retained MTAP expression. The median progression-free survival (PFS) was significantly shorter in patients with MTAP loss than those with MTAP retention (1.88 years vs. 6.80 years, p = 0.003). The median overall survival (OS) was also shorter in patients with MTAP loss than in MTAP-retaining counterparts (5.23 years vs. 10.69 years, p = 0.019). Multivariate analysis identified MTAP status (hazard ratio (HR), 0.081) and extent of resection (HR, 0.104) as independent prognostic factors for PFS. Astrocytomas lacking cytoplasmic MTAP expression showed a significantly higher median T/N ratio for 11C-methionine uptake than tumors retaining MTAP (2.12 vs. 1.65, p = 0.012). CONCLUSION: Our study revealed that the loss of MTAP expression correlates with poor prognosis and an elevated T/N ratio of 11C-methionine uptake in astrocytoma, IDH-mutant.


Subject(s)
Astrocytoma , Brain Neoplasms , Isocitrate Dehydrogenase , Methionine , Mutation , Purine-Nucleoside Phosphorylase , Humans , Purine-Nucleoside Phosphorylase/metabolism , Purine-Nucleoside Phosphorylase/genetics , Astrocytoma/genetics , Astrocytoma/metabolism , Astrocytoma/diagnostic imaging , Astrocytoma/pathology , Astrocytoma/mortality , Female , Male , Methionine/metabolism , Middle Aged , Brain Neoplasms/genetics , Brain Neoplasms/metabolism , Brain Neoplasms/diagnostic imaging , Brain Neoplasms/pathology , Brain Neoplasms/mortality , Prognosis , Isocitrate Dehydrogenase/genetics , Isocitrate Dehydrogenase/metabolism , Adult , Aged , Positron-Emission Tomography , Carbon Radioisotopes , Biomarkers, Tumor/metabolism , Biomarkers, Tumor/genetics , Young Adult
6.
Acta Neuropathol ; 146(3): 515-525, 2023 09.
Article in English | MEDLINE | ID: mdl-37524847

ABSTRACT

Malignant brain tumors, known as H3K27-altered diffuse midline glioma (DMG) and H3G34-mutant diffuse hemispheric glioma (DHG), can affect individuals of all ages and are classified as CNS WHO grade 4. We comprehensively characterized 390 H3F3A-mutant diffuse gliomas (201 females, 189 males) arising in pediatric patients (under 20 years old) and adults (20 years and older) evaluated by the CGP program at Foundation Medicine between 2013 and 2020. We assessed information from pathology reports, histopathology review, and clinical data. The cohort included 304 H3K27M-mutant DMG (156 females, 148 males) and 86 H3G34-mutant DHG (45 females, 41 males). Median patient age was 20 years (1-74 years). The frequency of H3K27M-mutant DMG was similar in both pediatric and adult patients in our cohort-48.6% of the patients were over 20 years old, 31.5% over 30, and 18% over 40 at initial diagnosis. FGFR1 hotspot point mutations (N546K and K656E) were exclusively identified in H3K27M-mutant DMG tumors (64/304, 21%; p = 0.0001); these tend to occur in older patients (median age: 32.5 years) and mainly arose in the diencephalon. H3K27M-mutant DMG had higher rates of mutations in NF1 (31.0 vs 8.1%; p = 0.0001) and PIK3CA/PIK3R1 (27.9% vs 15.1%; p = 0.016) compared to H3G34-mutant DHG. However, H3G34-mutant DHG had higher rates of targetable alterations in cell-cycle pathway genes (CDK4 and CDK6 amplification; CDKN2A/B deletion) (27.0 vs 9.0%). Potentially targetable PDGFRA alterations were identified in ~ 20% of both H3G34-mutant DHG and H3K27M-mutant DMG. Overall, in the present study H3K27M-mutant DMG occurred at similar rates in both adult and patient patients. Through our analysis, we were able to identify molecular features characteristic of DMG and DHG. By identifying the recurrent co-mutations including actionable FGFR1 point mutations found in nearly one-third of H3K27M-mutant DMG in young adults, our findings can inform clinical translational studies, patient diagnosis, and clinical trial design.


Subject(s)
Brain Neoplasms , Glioma , Adult , Aged , Child , Female , Humans , Male , Young Adult , Brain Neoplasms/genetics , Brain Neoplasms/pathology , Genomics , Glioma/genetics , Glioma/pathology , Histones/genetics , Mutation/genetics , World Health Organization , Infant , Child, Preschool , Adolescent , Middle Aged
7.
J Neurooncol ; 161(2): 193-202, 2023 Jan.
Article in English | MEDLINE | ID: mdl-35612696

ABSTRACT

OBJECTIVE: To evaluate the clinicopathological characteristics, radiology, and long-term outcomes of microcystic meningiomas (MM) and compare it with other subtypes of meningiomas managed at a single neurosurgical center. METHODS: A total of 87 consecutive patients who underwent surgical resection and were diagnosed as MM between 2005 and 2016 were enrolled for analysis. Clinicopathological, radiology, and prognostic information was collected and analyzed. Progression free survival (PFS) was compared with 659 patients with other subtypes of WHO grade 1 meningiomas and 167 patients with atypical meningiomas treated during the same period. RESULTS: Fifty six females and 31 males with MM were analyzed. Peri-tumor brain edema was frequent on T2 WI (85%).12 patients (13.8%) experienced tumor progression during the mean follow-up of 101.66 ± 40.92 months. The median PFS was unavailable, and the 5, 10, and 15 year progression-free rates were 96.9%, 84.0%, and 73.9%, respectively. Univariate COX analysis demonstrated skull base location and higher Ki-67 index as significant negative prognostic factors for PFS (P < 0.05); multivariate analysis identified tumor location and Ki-67 index as independent factors (P < 0.01), as well. Of note, the PFS of MM was worse than other WHO grade 1 subtypes (P < 0.001), but better than atypical meningiomas (P < 0.001), and the PFS differences were retained even when the analysis was limited to the patients receiving GTR (P < 0.05). CONCLUSION: The PFS of MM was worse than other WHO grade 1 subtypes and better than atypical meningiomas. Skull base location and higher Ki-67 index were independent negative prognostic factors in MM.


Subject(s)
Meningeal Neoplasms , Meningioma , Male , Female , Humans , Meningioma/diagnostic imaging , Meningioma/surgery , Meningeal Neoplasms/surgery , Meningeal Neoplasms/diagnosis , Ki-67 Antigen , Prognosis , World Health Organization
8.
J Neurooncol ; 161(2): 267-275, 2023 Jan.
Article in English | MEDLINE | ID: mdl-36329368

ABSTRACT

PURPOSE: To determine if loss of H3K27me3 could predict higher risk of re-recurrence in recurrent meningiomas. METHODS: A retrospective, single-center cohort study was performed for patients who underwent resection of recurrent grade 1 (N = 132) &2 (N = 32) meningiomas from 2009 to 2013. Association of H3K27me3 staining and clinical parameters was analyzed. Additionally, H3K27me3 staining was performed from 45 patients whose tumors recurred and were resected during the follow-up, to evaluate H3K27me3 change during tumor progression. Survival analysis was performed as well. RESULTS: Loss of H3K27me3 expression was observed in 83 patients, comprising 63 grade 1 (47.7%) and 20 grade 2 patients (62.5%). Both grade 1 (p < 0.001) and grade 2 recurrent meningiomas (p < 0.001) had a higher frequency of H3K27me3 loss, compared to de novo meningiomas. 8 of 27 tumors with retained H3K27me3 lost H3K27me3 during re-recurrence (29.6%), while no gain of H3K27me3 was observed in progressive disease from 18 tumors with H3K27me3 loss. Loss of H3K27me3 expression was associated with an earlier re-recurrence in recurrent meningiomas grade 1 and 2 (p < 0.001), and was an independent prognostic factor for PFS in recurrent grade 1 meningiomas (p = 0.005). CONCLUSION: Compared to primary meningiomas, recurrent meningiomas more predominantly had loss of H3K27me3 expression, and further loss can occur during the progression of recurrent tumors. Our results further demonstrated that loss of H3K27me3 predicted shorter PFS in recurrent grade 1 and grade 2 meningiomas. Our work thus supports clinical testing of H3K27me3 in recurrent meningiomas WHO grade 1 and 2.


Subject(s)
Meningeal Neoplasms , Meningioma , Humans , Meningioma/pathology , Histones , Meningeal Neoplasms/pathology , Cohort Studies , Prognosis , Retrospective Studies , Neoplasm Recurrence, Local/pathology , Biomarkers, Tumor/metabolism
9.
Stem Cells ; 39(6): 707-722, 2021 06.
Article in English | MEDLINE | ID: mdl-33586320

ABSTRACT

The coronavirus disease 2019 (COVID-19) pandemic has grown to be a global public health crisis with no safe and effective treatments available yet. Recent findings suggest that severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the coronavirus pathogen that causes COVID-19, could elicit a cytokine storm that drives edema, dysfunction of the airway exchange, and acute respiratory distress syndrome in the lung, followed by acute cardiac injury and thromboembolic events leading to multiorgan failure and death. Mesenchymal stem cells (MSCs), owing to their powerful immunomodulatory abilities, have the potential to attenuate the cytokine storm and have therefore been proposed as a potential therapeutic approach for which several clinical trials are underway. Given that intravenous infusion of MSCs results in a significant trapping in the lung, MSC therapy could directly mitigate inflammation, protect alveolar epithelial cells, and reverse lung dysfunction by normalizing the pulmonary microenvironment and preventing pulmonary fibrosis. In this review, we present an overview and perspectives of the SARS-CoV-2 induced inflammatory dysfunction and the potential of MSC immunomodulation for the prevention and treatment of COVID-19 related pulmonary disease.


Subject(s)
COVID-19/immunology , Cytokine Release Syndrome/immunology , Mesenchymal Stem Cells/immunology , SARS-CoV-2/immunology , COVID-19/therapy , COVID-19/virology , Cytokine Release Syndrome/therapy , Cytokine Release Syndrome/virology , Humans , Immunomodulation , Lung/immunology , Lung/pathology , Lung/virology , Mesenchymal Stem Cell Transplantation , Mesenchymal Stem Cells/virology , Pandemics , Pulmonary Fibrosis/immunology , Pulmonary Fibrosis/therapy , Pulmonary Fibrosis/virology , Respiratory Distress Syndrome/immunology , Respiratory Distress Syndrome/therapy , Respiratory Distress Syndrome/virology , SARS-CoV-2/genetics
10.
Neurosurg Focus ; 52(2): E6, 2022 02.
Article in English | MEDLINE | ID: mdl-35104795

ABSTRACT

Immunotherapy has emerged as a promising approach for treating aggressive solid tumors, even within the CNS. Mutation in the metabolic gene isocitrate dehydrogenase 1 (IDH1) represents not only a major glioma defining biomarker but also an attractive therapeutic neoantigen. As patients with IDH-mutant glioma enter early-phase vaccine and immune checkpoint inhibitor clinical trials, there is emerging evidence that implicates the oncometabolite, 2-hydroxyglutarate (2HG), generated by the neomorphic activity of mutant IDH, as a potential barrier to current immunotherapeutic approaches. Here, the authors review the immunomodulatory and immunosuppressive roles of 2HG within the unique IDH-mutant glioma tumor immune microenvironment and discuss promising immunotherapeutic approaches currently being investigated in preclinical models.


Subject(s)
Brain Neoplasms , Glioma , Brain Neoplasms/genetics , Brain Neoplasms/metabolism , Brain Neoplasms/therapy , Glioma/genetics , Glioma/therapy , Humans , Immunotherapy , Isocitrate Dehydrogenase/genetics , Mutation/genetics , Tumor Microenvironment
11.
Proc Natl Acad Sci U S A ; 115(36): E8388-E8394, 2018 09 04.
Article in English | MEDLINE | ID: mdl-30082399

ABSTRACT

Aggressive neurosurgical resection to achieve sustained local control is essential for prolonging survival in patients with lower-grade glioma. However, progression in many of these patients is characterized by local regrowth. Most lower-grade gliomas harbor isocitrate dehydrogenase 1 (IDH1) or IDH2 mutations, which sensitize to metabolism-altering agents. To improve local control of IDH mutant gliomas while avoiding systemic toxicity associated with metabolic therapies, we developed a precision intraoperative treatment that couples a rapid multiplexed genotyping tool with a sustained release microparticle (MP) drug delivery system containing an IDH-directed nicotinamide phosphoribosyltransferase (NAMPT) inhibitor (GMX-1778). We validated our genetic diagnostic tool on clinically annotated tumor specimens. GMX-1778 MPs showed mutant IDH genotype-specific toxicity in vitro and in vivo, inducing regression of orthotopic IDH mutant glioma murine models. Our strategy enables immediate intraoperative genotyping and local application of a genotype-specific treatment in surgical scenarios where local tumor control is paramount and systemic toxicity is therapeutically limiting.


Subject(s)
Brain Neoplasms , Cyanides/pharmacology , Genotype , Glioma , Guanidines/pharmacology , Isocitrate Dehydrogenase/genetics , Molecular Targeted Therapy/methods , Mutation , Neoplasm Proteins/genetics , Animals , Brain Neoplasms/drug therapy , Brain Neoplasms/enzymology , Brain Neoplasms/genetics , Drug Delivery Systems/methods , Female , Glioma/drug therapy , Glioma/enzymology , Glioma/genetics , Humans , Male , Mice , Mice, SCID , Xenograft Model Antitumor Assays
12.
J Neurooncol ; 147(2): 441-450, 2020 Apr.
Article in English | MEDLINE | ID: mdl-32088814

ABSTRACT

PURPOSE: The aim of this study was to systematically analyze the clinical characteristics of a large cohort of parasagittal meningioma (PM) and to evaluate the patients' outcomes and best treatment strategies based on tumor features. METHODS: To minimize selection bias we performed a single-institutional review of PM with restricted criteria. One hundred and ninety-two consecutive patients who met criteria for inclusion were reviewed from 2003 to 2011 in our general hospital. RESULTS: A total of 131 cases (68.2%) were with WHO grade I, while grade II and grade III PMs constituted 40 (20.8%) and 21 cases (10.9%). Higher histological grade was associated with loss of trimethylation of H3K27 (P = 0.000). For WHO grade I PMs, GTR was significantly associated with a better PFS (P = 0.023); however, adjuvant radiotherapy did not benefit patients with STR (P = 0.215). For de novo high-grade (WHO grade II and III) PMs (n = 37), adjuvant radiotherapy was associated with a significantly longer OS (P = 0.013), while no difference was observed between GTR and STR (P = 0.654). In recurrent high-grade PM patients (n = 24), GTR combined with adjuvant radiotherapy increased PFS (P = 0.005). CONCLUSIONS: This study demonstrated that PMs were a heterogeneous group of tumors with a high proportion of high-grade tumors that often displayed aggressive clinical behaviors. Low-grade PM benefited from radical resection, whereas high-grade de novo PM did not. Adjuvant radiotherapy significantly prolonged OS for high-grade primary PM, but did not impact survival of patients with subtotally resected low-grade tumors. Long-term outcome of high-grade recurrent PMs was dismal. We thus show that extent of tumor resection, tumor grade and tumor recurrent status inform therapeutic decisions for PMs.


Subject(s)
Meningeal Neoplasms/mortality , Meningioma/mortality , Adolescent , Adult , Aged , Aged, 80 and over , Combined Modality Therapy , Disease Management , Female , Follow-Up Studies , Humans , Male , Meningeal Neoplasms/pathology , Meningeal Neoplasms/therapy , Meningioma/pathology , Meningioma/therapy , Middle Aged , Prognosis , Retrospective Studies , Survival Rate , Young Adult
14.
Proc Natl Acad Sci U S A ; 114(30): E6157-E6165, 2017 07 25.
Article in English | MEDLINE | ID: mdl-28710334

ABSTRACT

The recent Food and Drug Administration approval of immunogenic oncolytic virus (OV) has opened a new era in the treatment of advanced melanoma; however, approximately 50% of patients with melanoma develop brain metastasis, and currently there are no beneficial treatment options for such patients. To model the progression of metastases seen in patients and to overcome the hurdles of systemic delivery of OV, we developed melanoma brain metastasis models in immunocompromised and immunocompetent mice, and tested the fate and efficacy of oncolytic herpes simplex virus (oHSV)-armed mesenchymal stem cells (MSCs). Using brain-seeking patient-derived melanoma cells and real-time in vivo imaging, we show a widespread distribution of micrometastases and macrometastases in the brain, recapitulating the progression of multifoci metastases seen in patients. We armed MSCs with different oHSV variants (MSC-oHSV) and found that intracarotid administration of MSC-oHSV, but not of purified oHSV alone, effectively tracks metastatic tumor lesions and significantly prolongs the survival of brain tumor-bearing mice. In a syngeneic model of melanoma brain metastasis, a combination of MSC-oHSV and PD-L1 blockade increases IFNγ-producing CD8+ tumor-infiltrating T lymphocytes and results in a profound extension of the median survival of treated animals. This study thus demonstrates the utility of MSCs as OV carriers to disseminated brain lesions, and provides a clinically applicable therapeutic platform to target melanoma brain metastasis.


Subject(s)
Brain Neoplasms/therapy , Melanoma, Experimental/therapy , Mesenchymal Stem Cells , Oncolytic Virotherapy/methods , Animals , Brain Neoplasms/pathology , Cell Line , Humans , Mice , Neoplasm Metastasis , Oncolytic Viruses/genetics , Simplexvirus/genetics , Tumor Cells, Cultured
15.
J Virol ; 92(15)2018 08 01.
Article in English | MEDLINE | ID: mdl-29793956

ABSTRACT

Oncolytic viruses, including herpes simplex viruses (HSVs), are a new class of cancer therapeutic engineered to infect and kill cancer cells while sparing normal tissue. To ensure that oncolytic HSV (oHSV) is safe in the brain, all oHSVs in clinical trial for glioma lack the γ34.5 genes responsible for neurovirulence. However, loss of γ34.5 attenuates growth in cancer cells. Glioblastoma (GBM) is a lethal brain tumor that is heterogeneous and contains a subpopulation of cancer stem cells, termed GBM stem-like cells (GSCs), that likely promote tumor progression and recurrence. GSCs and matched serum-cultured GBM cells (ScGCs), representative of bulk or differentiated tumor cells, were isolated from the same patient tumor specimens. ScGCs are permissive to replication and cell killing by oHSV with deletion of the γ34.5 genes (γ34.5- oHSV), while patient-matched GSCs were not, implying an underlying biological difference between stem and bulk cancer cells. GSCs specifically restrict the synthesis of HSV-1 true late (TL) proteins, without affecting viral DNA replication or transcription of TL genes. A global shutoff of cellular protein synthesis also occurs late after γ34.5- oHSV infection of GSCs but does not affect the synthesis of early and leaky late viral proteins. Levels of phosphorylated eIF2α and eIF4E do not correlate with cell permissivity. Expression of Us11 in GSCs rescues replication of γ34.5- oHSV. The difference in degrees of permissivity between GSCs and ScGCs to γ34.5- oHSV illustrates a selective translational regulatory pathway in GSCs that may be operative in other stem-like cells and has implications for creating oHSVs.IMPORTANCE Herpes simplex virus (HSV) can be genetically engineered to endow cancer-selective replication and oncolytic activity. γ34.5, a key neurovirulence gene, has been deleted in all oncolytic HSVs in clinical trial for glioma. Glioblastoma stem-like cells (GSCs) are a subpopulation of tumor cells thought to drive tumor heterogeneity and therapeutic resistance. GSCs are nonpermissive for γ34.5- HSV, while non-stem-like cancer cells from the same patient tumors are permissive. GSCs restrict true late protein synthesis, despite normal viral DNA replication and transcription of all kinetic classes. This is specific for true late translation as early and leaky late transcripts are translated late in infection, notwithstanding shutoff of cellular protein synthesis. Expression of Us11 in GSCs rescues the replication of γ34.5- HSV. We have identified a cell type-specific innate response to HSV-1 that limits oncolytic activity in glioblastoma.


Subject(s)
Brain Neoplasms/virology , Gene Deletion , Glioblastoma/virology , Neoplastic Stem Cells/virology , Simplexvirus/physiology , Viral Proteins/genetics , Animals , Brain Neoplasms/metabolism , Brain Neoplasms/therapy , Cell Culture Techniques/methods , Cell Line, Tumor , Chlorocebus aethiops , Glioblastoma/metabolism , Glioblastoma/therapy , Herpes Simplex/genetics , Neoplastic Stem Cells/metabolism , Oncolytic Viruses/genetics , Oncolytic Viruses/physiology , RNA-Binding Proteins/metabolism , Simplexvirus/genetics , Vero Cells , Viral Proteins/metabolism , Virus Replication
16.
Proc Natl Acad Sci U S A ; 113(16): 4476-81, 2016 Apr 19.
Article in English | MEDLINE | ID: mdl-27044098

ABSTRACT

Inhibition of the vascular endothelial growth factor (VEGF) pathway has failed to improve overall survival of patients with glioblastoma (GBM). We previously showed that angiopoietin-2 (Ang-2) overexpression compromised the benefit from anti-VEGF therapy in a preclinical GBM model. Here we investigated whether dual Ang-2/VEGF inhibition could overcome resistance to anti-VEGF treatment. We treated mice bearing orthotopic syngeneic (Gl261) GBMs or human (MGG8) GBM xenografts with antibodies inhibiting VEGF (B20), or Ang-2/VEGF (CrossMab, A2V). We examined the effects of treatment on the tumor vasculature, immune cell populations, tumor growth, and survival in both the Gl261 and MGG8 tumor models. We found that in the Gl261 model, which displays a highly abnormal tumor vasculature, A2V decreased vessel density, delayed tumor growth, and prolonged survival compared with B20. In the MGG8 model, which displays a low degree of vessel abnormality, A2V induced no significant changes in the tumor vasculature but still prolonged survival. In both the Gl261 and MGG8 models A2V reprogrammed protumor M2 macrophages toward the antitumor M1 phenotype. Our findings indicate that A2V may prolong survival in mice with GBM by reprogramming the tumor immune microenvironment and delaying tumor growth.


Subject(s)
Antibodies, Bispecific/pharmacology , Antibodies, Neoplasm/pharmacology , Antineoplastic Agents/pharmacology , Glioblastoma/drug therapy , Macrophages/metabolism , Neoplasm Proteins/antagonists & inhibitors , Neoplasms, Experimental/drug therapy , Ribonuclease, Pancreatic/antagonists & inhibitors , Vascular Endothelial Growth Factor A/antagonists & inhibitors , Vesicular Transport Proteins/antagonists & inhibitors , Animals , Cell Line, Tumor , Glioblastoma/metabolism , Glioblastoma/pathology , Humans , Macrophages/pathology , Mice , Neoplasm Proteins/metabolism , Neoplasms, Experimental/metabolism , Neoplasms, Experimental/pathology , Ribonuclease, Pancreatic/metabolism , Vascular Endothelial Growth Factor A/metabolism , Vesicular Transport Proteins/metabolism , Xenograft Model Antitumor Assays
17.
Acta Neuropathol ; 136(5): 779-792, 2018 11.
Article in English | MEDLINE | ID: mdl-30123936

ABSTRACT

Progressive meningiomas that have failed surgery and radiation have a poor prognosis and no standard therapy. While meningiomas are more common in females overall, progressive meningiomas are enriched in males. We performed a comprehensive molecular characterization of 169 meningiomas from 53 patients with progressive/high-grade tumors, including matched primary and recurrent samples. Exome sequencing in an initial cohort (n = 24) detected frequent alterations in genes residing on the X chromosome, with somatic intragenic deletions of the dystrophin-encoding and muscular dystrophy-associated DMD gene as the most common alteration (n = 5, 20.8%), along with alterations of other known X-linked cancer-related genes KDM6A (n =2, 8.3%), DDX3X, RBM10 and STAG2 (n = 1, 4.1% each). DMD inactivation (by genomic deletion or loss of protein expression) was ultimately detected in 17/53 progressive meningioma patients (32%). Importantly, patients with tumors harboring DMD inactivation had a shorter overall survival (OS) than their wild-type counterparts [5.1 years (95% CI 1.3-9.0) vs. median not reached (95% CI 2.9-not reached, p = 0.006)]. Given the known poor prognostic association of TERT alterations in these tumors, we also assessed for these events, and found seven patients with TERT promoter mutations and three with TERT rearrangements in this cohort (n = 10, 18.8%), including a recurrent novel RETREG1-TERT rearrangement that was present in two patients. In a multivariate model, DMD inactivation (p = 0.033, HR = 2.6, 95% CI 1.0-6.6) and TERT alterations (p = 0.005, HR = 3.8, 95% CI 1.5-9.9) were mutually independent in predicting unfavorable outcomes. Thus, DMD alterations identify a subset of progressive/high-grade meningiomas with worse outcomes.


Subject(s)
Dystrophin/genetics , Gene Deletion , Meningeal Neoplasms/genetics , Meningioma/genetics , Aged , Aged, 80 and over , Cell Line, Tumor/pathology , Cell Line, Tumor/ultrastructure , Cohort Studies , Disease Progression , Dystrophin/metabolism , Female , Humans , Magnetic Resonance Imaging , Male , Meningeal Neoplasms/diagnostic imaging , Meningeal Neoplasms/pathology , Meningioma/diagnostic imaging , Meningioma/pathology , Microscopy, Electron, Transmission , Middle Aged , Multiplex Polymerase Chain Reaction , RNA, Messenger/metabolism , Sex Chromatin/genetics , Telomerase/genetics , Telomerase/metabolism , Exome Sequencing
18.
J Neurooncol ; 140(3): 639-647, 2018 Dec.
Article in English | MEDLINE | ID: mdl-30209689

ABSTRACT

PURPOSE: The aim of this study was to thoroughly analyze the clinical characteristics of a large cohort of spinal meningioma (SM) from a single neurological center and identify risk factors associated with worse progression free survival and neurological function outcome. METHODS: Clinical information was retrieved from 483 SM and 9806 cranial meningioma cases who were operated in our center between 2003 and 2013. 194 SM patients who were followed at the main branch were used for prognostic analyses that included both recurrence free survival and neurological functions based on Modified McCormick scale (MMS). RESULTS: Females were predominant (P < 0.001). High grade tumors were not common (WHO grade II, 2.9%; grade III, 1.7%), while the clear cell subtype was frequent within grade II SMs (6/14, 42.9%). Macroscopic total resection was achieved in all SMs (Simpson grade I, 30.9%; grade II, 65.5%; grade III, 3.6%) with a low complications rate (4.6%) and provided neurological improvement in 80 patients (41.2%). Recurrence was seen in 9 cases (4.6%) and associated with high WHO grade, male, prior recurrence, and Simpson grade III. High WHO grade and high Ki-67 index were identified to be independent factors predictive of both neurological function deterioration and impaired post-operative neurological status. CONCLUSIONS: Our analysis of the largest SM cohort in scale from a single institution offers a comprehensive view of the clinical characteristics of surgically treated SM, revealing the distinct biology of SM in comparison to its cranial counterparts, and providing guidance to improve surgical management of SM.


Subject(s)
Meningeal Neoplasms/diagnosis , Meningeal Neoplasms/surgery , Meningioma/diagnosis , Meningioma/surgery , Adolescent , Adult , Aged , Aged, 80 and over , Child , Child, Preschool , Cohort Studies , Female , Humans , Male , Meningeal Neoplasms/epidemiology , Meningioma/epidemiology , Middle Aged , Neoplasm Recurrence, Local/diagnosis , Neoplasm Recurrence, Local/epidemiology , Neoplasm Recurrence, Local/surgery , Prognosis , Progression-Free Survival , Risk Factors , Young Adult
19.
Int J Cancer ; 141(8): 1671-1681, 2017 10 15.
Article in English | MEDLINE | ID: mdl-28567859

ABSTRACT

Temozolomide (TMZ) chemotherapy, in combination with maximal safe resection and radiotherapy, is the current standard of care for patients with glioblastoma (GBM). Despite this multimodal approach, GBM inevitably relapses primarily due to resistance to chemo-radiotherapy, and effective treatment is not available for recurrent disease. In this study we identified TMZ resistant patient-derived primary and previously treated recurrent GBM stem cells (GSC), and investigated the therapeutic activity of a pro-apoptotic variant of oHSV (oHSV-TRAIL) in vitro and in vivo. We show that oHSV-TRAIL modulates cell survival and MAP Kinase proliferation signaling pathways as well as DNA damage response pathways in both primary and recurrent TMZ-resistant GSC. Utilizing real time in vivo imaging and correlative immunohistochemistry, we show that oHSV-TRAIL potently inhibits tumor growth and extends survival of mice bearing TMZ-insensitive recurrent intracerebral GSC tumors via robust and selective induction of apoptosis-mediated death in tumor cells, resulting in cures in 40% of the treated mice. In comparison, the anti-tumor effects in a primary chemoresistant GSC GBM model exhibiting a highly invasive phenotype were significant but less prominent. This work thus demonstrates the ability of oHSV-TRAIL to overcome the therapeutic resistance and recurrence of GBM, and provides a basis for its testing in a GBM clinical trial.


Subject(s)
Brain Neoplasms/therapy , Glioblastoma/therapy , Neoplastic Stem Cells/virology , Oncolytic Virotherapy/methods , Simplexvirus/physiology , Animals , Apoptosis/physiology , Brain Neoplasms/drug therapy , Brain Neoplasms/virology , Cell Line, Tumor , Cohort Studies , Dacarbazine/analogs & derivatives , Dacarbazine/pharmacology , Drug Resistance, Neoplasm , Glioblastoma/drug therapy , Glioblastoma/virology , HEK293 Cells , Humans , Mice , Neoplasm Recurrence, Local/drug therapy , Neoplasm Recurrence, Local/therapy , Neoplasm Recurrence, Local/virology , Neoplastic Stem Cells/drug effects , Neoplastic Stem Cells/pathology , Simplexvirus/genetics , TNF-Related Apoptosis-Inducing Ligand/biosynthesis , TNF-Related Apoptosis-Inducing Ligand/genetics , Temozolomide
20.
Int J Cancer ; 141(11): 2348-2358, 2017 12 01.
Article in English | MEDLINE | ID: mdl-28801914

ABSTRACT

Despite the current standard of multimodal management, glioblastoma (GBM) inevitably recurs and effective therapy is not available for recurrent disease. A subset of tumor cells with stem-like properties, termed GBM stem-like cells (GSCs), are considered to play a role in tumor relapse. Although oncolytic herpes simplex virus (oHSV) is a promising therapeutic for GBM, its efficacy against recurrent GBM is incompletely characterized. Transforming growth factor beta (TGF-ß) plays vital roles in maintaining GSC stemness and GBM pathogenesis. We hypothesized that oHSV and TGF-ß inhibitors would synergistically exert antitumor effects for recurrent GBM. Here we established a panel of patient-derived recurrent tumor models from GBMs that relapsed after postsurgical radiation and chemotherapy, based on GSC-enriched tumor sphere cultures. These GSCs are resistant to the standard-of-care temozolomide but susceptible to oHSVs G47Δ and MG18L. Inhibition of TGF-ß receptor kinase with selective targeted small molecules reduced clonogenic sphere formation in all tested recurrent GSCs. The combination of oHSV and TGF-ßR inhibitor was synergistic in killing recurrent GSCs through, in part, an inhibitor-induced JNK-MAPK blockade and increase in oHSV replication. In vivo, systemic treatment with TGF-ßR inhibitor greatly enhanced the antitumor effects of single intratumoral oHSV injections, resulting in cures in 60% of mice bearing orthotopic recurrent GBM. These results reveal a novel synergistic interaction of oHSV therapy and TGF-ß signaling blockade, and warrant further investigations aimed at clinical translation of this combination strategy for GBM patients.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/pharmacology , Brain Neoplasms/pathology , Glioblastoma/pathology , Oncolytic Virotherapy/methods , Transforming Growth Factor beta/antagonists & inhibitors , Animals , Blotting, Western , Humans , Immunohistochemistry , Mice , Mice, SCID , Neoplastic Stem Cells/drug effects , Neoplastic Stem Cells/pathology , Real-Time Polymerase Chain Reaction , Signal Transduction/drug effects , Simplexvirus , Xenograft Model Antitumor Assays
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