Bret Mobley

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University of Memphis

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Santa Clara University

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Papers by Bret Mobley

111 Integrating multidimensional mass cytometry and multiplex immunohistochemistry to infer spatial relationships between human glioblastoma infiltrating immune cells that correlate with patient outcome

Regular and Young Investigator Award Abstracts, Nov 1, 2022

Consent No sensitive or identifiable information is included in this study.

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TMIC-26. Using Integrated Multidimensional Mass Cytometry and Multiplex Immunohistochemistry to Infer Spatial Relationships Between Phenotypically Distinct Glioblastoma Infiltrating Immune Cells

Neuro-Oncology

Glioblastomas (GBM) account for ~60% of adult primary brain tumors. With few advances in therapeu... more Glioblastomas (GBM) account for ~60% of adult primary brain tumors. With few advances in therapeutics, median overall survival remains 15-months post-diagnosis. Immunotherapies may provide therapeutic benefit; however, no predictive immune features have informed therapeutic stratification. Radiographic tumor contact with the lateral ventricle (C-GBM) correlates with 7-months worse prognosis compared to patients with ventricle non-contacting GBM (NC-GBM), yet the influence of ventricle contact on anti-tumor immunity is unknown. This study characterized the GBM immune microenvironment and identified targetable mechanisms of immunosuppression correlating with worse outcomes in C-GBM patients.Primary glioblastoma tissue was provided with written informed consent in accordance with the Declaration of Helsinki and with approval of the Vanderbilt Institutional Review Board (IRB #131870). Seventeen patients presented with primary, IDH-wildtype C-GBM and 15 with NC-GBM. Machine learning inte...

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Papillary tumor of the spinal cord. Report of two cases

The FASEB Journal, 2008

Primary Intracranial Sarcoma, DICER1-Mutant Presenting as a Pineal Region Tumor Mimicking Pineoblastoma: Case Report and Review of the Literature

Journal of Neuropathology & Experimental Neurology

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IMMU-11. Selective Enrichment of Suppressed Immune Cells in the Tumor Microenvironment Correlates with Establishment of Distinct Immunologic Niches in Human Glioblastomas Contacting the Lateral Ventricle

Neuro-Oncology, 2021

Glioblastomas (GBM) account for 60% of adult primary brain tumors. With few advances in therapeut... more Glioblastomas (GBM) account for 60% of adult primary brain tumors. With few advances in therapeutics, median overall survival remains 15-months post-diagnosis. Immunotherapies may provide therapeutic benefit in GBM patients; however, no predictive immune features currently inform therapeutic stratification in GBM. We have shown that, independently of known prognosticators, radiographic tumor contact with the lateral ventricle (C-GBM) correlates with 7-months worse prognosis compared to patients with ventricle non-contacting GBM (NC-GBM). This study sought to characterize the GBM immune microenvironment and identify targetable mechanisms of immunosuppression correlating with worse outcomes in C-GBM. Primary glioblastoma specimens were resected in accordance with the Declaration of Helsinki (IRB #131870). Twelve patients presented with C-GBM and thirteen with NC-GBM. Machine learning tools applied to mass cytometry data characterized tumor-infiltrating immune populations and identifie...

RBFOX1 is regulated by the adenosine 2a receptor and is ubiquitinated in tau tangles in Alzheimer’s disease

Alzheimer's & Dementia, 2021

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Additional file 6: of Genomic analysis demonstrates that histologically-defined astroblastomas are molecularly heterogeneous and that tumors with MN1 rearrangement exhibit the most favorable prognosis

Table S2. Patient Treatment and Survival Data. (DOCX 25 kb)

Additional file 4: of Genomic analysis demonstrates that histologically-defined astroblastomas are molecularly heterogeneous and that tumors with MN1 rearrangement exhibit the most favorable prognosis

Figure S3. Example images of MN1 FISH. (A) Case C10 showing red and green break apart probes (arr... more Figure S3. Example images of MN1 FISH. (A) Case C10 showing red and green break apart probes (arrows) and yellow intact MN1 loci (arrowheads). (B) Case C3 with displaced green probe only indicating an unbalanced translocation (arrows). (C) Case C23 showing intact MN1 loci. (D) Case C11 showing multiple intact MN1 loci per nucleus indicating chromosome 22 polyploidy. (EPS 23150 kb)

Additional file 3: of Genomic analysis demonstrates that histologically-defined astroblastomas are molecularly heterogeneous and that tumors with MN1 rearrangement exhibit the most favorable prognosis

Table S1. Tumor DNA methylation class probabilities from the random forest methylation class pred... more

Additional file 2: of Genomic analysis demonstrates that histologically-defined astroblastomas are molecularly heterogeneous and that tumors with MN1 rearrangement exhibit the most favorable prognosis

Figure S2. Heatmap from unsupervised hierarchical clustering of ABs with selected reference tumor... more

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Additional file 1: of Genomic analysis demonstrates that histologically-defined astroblastomas are molecularly heterogeneous and that tumors with MN1 rearrangement exhibit the most favorable prognosis

Figure S1. Unsupervised t-SNE analysis of ABs with the entire Capper et al. dataset [5]. DNA meth... more Figure S1. Unsupervised t-SNE analysis of ABs with the entire Capper et al. dataset [5]. DNA methylation profiles from ABs were analyzed with the comprehensive Capper et al. dataset using the top 32,000 probes. (A). ABs did not group into a single methylation class, but instead grouped within the methylation classes designated (B) EPN-RELA, (C) PXA, (D) HGNET-MN1, (E) CONTR-REACT and LGG-PA/ST-GG, and (F) CONTR-HEMI. (EPS 5516 kb)

Genomic analysis demonstrates that histologically-defined astroblastomas are molecularly heterogeneous and that tumors with MN1 rearrangement exhibit the most favorable prognosis

Acta Neuropathologica Communications

Astroblastoma (AB) is a rare CNS tumor demonstrating abundant astroblastomatous pseudorosettes. I... more Astroblastoma (AB) is a rare CNS tumor demonstrating abundant astroblastomatous pseudorosettes. Its molecular features have not been comprehensively studied and its status as a tumor entity is controversial. We analyzed a cohort of 27 histologically-defined ABs using DNA methylation profiling, copy number analysis, FISH and sitedirected sequencing. Most cases demonstrated mutually exclusive MN1 rearrangements (n = 10) or BRAF V600E mutations (n = 7). Two additional cases harbored RELA rearrangements. Other cases lacked these specific genetic alterations (n = 8). By DNA methylation profiling, tumors with MN1 or RELA rearrangement clustered with highgrade neuroepithelial tumor with MN1 alteration (HGNET-MN1) and RELA-fusion ependymoma, respectively. In contrast, BRAF V600E-mutant tumors grouped with pleomorphic xanthoastrocytoma (PXA). Six additional tumors clustered with either supratentorial pilocytic astrocytoma and ganglioglioma (LGG-PA/GG-ST), normal or reactive cerebrum, or with no defined DNA methylation class. While certain histologic features favored one genetic group over another, no group could be reliably distinguished by histopathology alone. Survival analysis between genetic AB subtypes was limited by sample size, but showed that MN1-rearranged AB tumors were characterized by better overall survival compared to other genetic subtypes, in fact, significantly better than BRAF V600E-mutant tumors (P = 0.013). Our data confirm that histologically-defined ABs are molecularly heterogeneous and do not represent a single entity. They rather encompass several low-to higher-grade glial tumors including neuroepithelial tumors with MN1 rearrangement, PXA-like tumors, RELA ependymomas, and possibly yet uncharacterized lesions. Genetic subtyping of tumors exhibiting AB histology, particularly determination of MN1 and BRAF V600E status, is necessary for important prognostic and possible treatment implications.

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Mutation Status and Epithelial Differentiation Stratify Recurrence Risk in Chordoid Meningioma—A Multicenter Study with High Prognostic Relevance

Cancers, Jan 17, 2020

Chordoid meningioma is a rare WHO grade II histologic variant. Its molecular alterations or their... more Chordoid meningioma is a rare WHO grade II histologic variant. Its molecular alterations or their impact on patient risk stratification have not been fully explored. We performed a multicenter, clinical, histological, and genomic analysis of chordoid meningiomas from 30 patients (34 tumors), representing the largest integrated study to date. By NHERF1 microlumen immunohistochemical detection, three epithelial differentiation (ED) groups emerged: #1/fibroblastic-like, #2/epithelial-poorly-differentiated and #3/epithelial-well-differentiated. These ED groups correlated with tumor location and genetic profiling, with NF2 and chromatin remodeling gene mutations clustering in ED group #2, and TRAF7 mutations segregating in ED group #3. Mutations in LRP1B were found in the largest number of cases (36%) across ED groups #2 and #3. Pathogenic ATM and VHL germline mutations occurred in ED group #3 patients, conferring an aggressive or benign course, respectively. The recurrence rate significantly correlated with mutations in NF2, as single gene, and with mutations in chromatin remodeling and DNA damage response genes, as groups. The recurrence rate was very high in ED group #2, moderate in ED group #3, and absent in ED group #1. This study proposes guidelines for tumor recurrence risk stratification and practical considerations for patient management.

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38 Spatial immune profiling of human glioblastoma tissue reveals the presence of aggregated lymphoid niches in the tumor microenvironment

Journal for ImmunoTherapy of Cancer

BackgroundGlioblastomas (GBM) account for 60% of adult primary brain tumors. With few advances in... more BackgroundGlioblastomas (GBM) account for 60% of adult primary brain tumors. With few advances in therapeutics, median overall survival remains 15-months post-diagnosis. Immunotherapies may provide therapeutic benefit in GBM patients; however, no predictive immune features currently inform therapeutic stratification in GBM. We have shown that, independently of known prognosticators, radiographic tumor contact with the lateral ventricle (C-GBM) correlates with 7-months worse survival prognosis compared to patients with ventricle non-contacting GBM (NC-GBM). This study sought to characterize the GBM immune microenvironment and identify targetable mechanisms of immunosuppression correlating with worse outcomes in C-GBM.MethodsTwelve patients presented with pathologically confirmed primary, IDH wildtype C-GBM and thirteen with NC-GBM. Multiplex immunohistochemistry (mxIHC) was performed on formalin-fixed paraffin embedded (FFPE) tissue for each patient interrogating 8 predictive immune ...

661 Five immunotypic signatures identified in human glioblastoma correlate with tumor contact with the lateral ventricle, immune suppression, and patient outcome

Journal for ImmunoTherapy of Cancer

BackgroundGlioblastomas make up more than 60% of adult primary brain tumors and carry a median su... more BackgroundGlioblastomas make up more than 60% of adult primary brain tumors and carry a median survival of less than 15 months despite aggressive therapy. Immunotherapy, now standard of care for many peripheral solid tumors, offers an appealing alternative platform that may improve survival outcomes for patients with glioblastoma; however, predictive features that could inform responsiveness to different immunotherapeutic modalities remains to be elucidated. Recent studies have demonstrated that patients whose tumors show radiographic contact with the lateral ventricle have diminished survival outcomes compared to patients whose tumors do not contact the lateral ventricle. While greater immune infiltrate correlates with more favorable outcomes and more effectual responses to immunotherapy, the anti-tumor immune response in the ventricle is unknown. We hypothesized that ventricle contact may provide a uniquely immunosuppressive microenvironment within the brain that promotes tumor gr...

IMMU-16. Two Distinct Subsets of Natural Killer Cells Are Enriched in the Tumor Microenvironment and Correlate with Survival Outcome in Human Glioblastoma

Neuro-Oncology

Glioblastomas (GBM) account for up to 60% of all adult primary brain tumors. With few advances in... more Glioblastomas (GBM) account for up to 60% of all adult primary brain tumors. With few advances in therapeutics, median overall survival (mOS) remains at 15-months post diagnosis. Success of immunotherapy in peripheral solid tumors may offer an alternative therapeutic approach for patients with GBM tumors; however, no predictive immune features currently inform therapeutic stratification for GBM. Recently, we have identified radiographic tumor contact with the lateral ventricle (LV) as a prognostic indicator of OS, as patients with LV+ GBM survive 7 months less than patients with LV- gliomas. This disparity was independent of known prognostic factors (e.g. KPS, extent of resection). Further, we have identified a correlation between greater immune infiltration and the frequency of tumor subtypes with more favorable prognosis. We therefore hypothesized that differences in overall survival between patients with LV+ and LV- are due, in part, to a uniquely immunosuppressive microenvironme...

Sustained response to erlotinib and rapamycin in a patient with pediatric anaplastic oligodendroglioma

Pediatric Blood & Cancer

COMP-11. Single Cell Mass Cytometry Signaling Profiles and a Novel Computational Tool Identify High Risk Glioblastoma Cells

Neuro-Oncology

In glioblastoma, changes in signaling, gene sequence, copy number, or transcript expression can d... more In glioblastoma, changes in signaling, gene sequence, copy number, or transcript expression can define patient subgroups, but these subgroups are not yet associated with differential outcome for most patients with high-risk, IDH wild-type disease. Single cell interrogation of phospho-protein signaling has successfully revealed novel cell types associated with patient outcomes in blood cancers, suggesting that a comparable approach could be used in brain tumors. The goal of this study was to combine a single cell phospho-protein profiling approach with novel, automated computational analysis to identify abnormal glioblastoma cells that stratify patient clinical risk. Effective tissue dissociation strategies and validated antibody panels were created for mass cytometry analyses of resected glioblastoma tissue. These panels simultaneously measured 45 determinants of neural and glioma cell identity, including transcription factors, phospho-proteins, and surface receptors. 28 glioblastom...

IMMU-37. Single-Cell Systems Neuroimmunology Reveals Immunosuppressive Correlates with Ventricular Stem Cell Niche Contact in Human Glioblastoma

Neuro-Oncology

Glioblastomas make up more than 60% of adult primary brain tumors and carry a median survival of ... more Glioblastomas make up more than 60% of adult primary brain tumors and carry a median survival of less than 15 months despite aggressive standard therapy. Immunotherapy, which is now standard of care for many solid tumors, offers an appealing therapeutic approach that may improve outcomes for glioblastoma patients. Predictive features in glioblastomas that may inform responsiveness to different immunotherapeutic modalities, however, are still lacking. Recent studies have demonstrated that patients whose tumors show radiographic contact with the lateral ventricles, and thus the stem cell niche of the ventricular-subventricular zone (V-SVZ), have reduced survival outcomes compared to patients whose tumors do not contact the V-SVZ. We therefore hypothesized that tumor contact with the V-SVZ engenders a unique, immunosuppressive microenvironment that promotes tumor growth by suppressing anti-tumor immunity. Glioblastoma tumors, obtained in accordance with the Declaration of Helsinki and ...

Molecular characterization of immune-related severe adverse events (irSAE)

Journal of Clinical Oncology

3076 Background: Immune checkpoint inhibitors (ICIs; anti-CTLA-4 and anti-PD-1) have shown clinic... more 3076 Background: Immune checkpoint inhibitors (ICIs; anti-CTLA-4 and anti-PD-1) have shown clinical success in many cancers, but may cause rare irSAE. The molecular features of irSAE have not been extensively explored. Therefore, we characterized the immune composition of tissue affected by ICI-mediated inflammation with a focus on colitis and neurologic toxicity. Methods: We performed retrospective T-cell receptor (TCRβ) sequencing, RNA-sequencing (HTG EdgeSeq; > 2500 immune-related genes), and digital spatial profiling (NanoString) for 20 protein markers in 10 regions across tissues representing ICI-induced colitis, autoimmune inflammation (e.g. Crohn’s) and normal colon. Matched tumors were also included in a subset. We also analyzed the encephalitic and healthy brain of a unique presentation of anti-PD-1-induced encephalitis. Results: Patient-matched melanoma and colitis biopsies (n = 3) demonstrated shared T cell clones in all samples ranging from several shared clones to se...

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Regular and Young Investigator Award Abstracts, Nov 1, 2022

Consent No sensitive or identifiable information is included in this study.

Download

TMIC-26. Using Integrated Multidimensional Mass Cytometry and Multiplex Immunohistochemistry to Infer Spatial Relationships Between Phenotypically Distinct Glioblastoma Infiltrating Immune Cells

Neuro-Oncology

Download

Papillary tumor of the spinal cord. Report of two cases

The FASEB Journal, 2008

Primary Intracranial Sarcoma, DICER1-Mutant Presenting as a Pineal Region Tumor Mimicking Pineoblastoma: Case Report and Review of the Literature

Journal of Neuropathology & Experimental Neurology

Download

Neuro-Oncology, 2021

RBFOX1 is regulated by the adenosine 2a receptor and is ubiquitinated in tau tangles in Alzheimer’s disease

Alzheimer's & Dementia, 2021

Download

Table S2. Patient Treatment and Survival Data. (DOCX 25 kb)

Table S1. Tumor DNA methylation class probabilities from the random forest methylation class pred... more

Figure S2. Heatmap from unsupervised hierarchical clustering of ABs with selected reference tumor... more

Download

Genomic analysis demonstrates that histologically-defined astroblastomas are molecularly heterogeneous and that tumors with MN1 rearrangement exhibit the most favorable prognosis

Acta Neuropathologica Communications

Download

Mutation Status and Epithelial Differentiation Stratify Recurrence Risk in Chordoid Meningioma—A Multicenter Study with High Prognostic Relevance

Cancers, Jan 17, 2020

Download

38 Spatial immune profiling of human glioblastoma tissue reveals the presence of aggregated lymphoid niches in the tumor microenvironment

Journal for ImmunoTherapy of Cancer

661 Five immunotypic signatures identified in human glioblastoma correlate with tumor contact with the lateral ventricle, immune suppression, and patient outcome

Journal for ImmunoTherapy of Cancer

IMMU-16. Two Distinct Subsets of Natural Killer Cells Are Enriched in the Tumor Microenvironment and Correlate with Survival Outcome in Human Glioblastoma

Neuro-Oncology

Sustained response to erlotinib and rapamycin in a patient with pediatric anaplastic oligodendroglioma

Pediatric Blood & Cancer

COMP-11. Single Cell Mass Cytometry Signaling Profiles and a Novel Computational Tool Identify High Risk Glioblastoma Cells

Neuro-Oncology

IMMU-37. Single-Cell Systems Neuroimmunology Reveals Immunosuppressive Correlates with Ventricular Stem Cell Niche Contact in Human Glioblastoma

Neuro-Oncology

Molecular characterization of immune-related severe adverse events (irSAE)

Journal of Clinical Oncology

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