41 results on '"Mahmoud S. Alghamri"'
Search Results
2. Impact of epigenetic reprogramming on antitumor immune responses in glioma
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Brandon L. McClellan, Santiago Haase, Felipe J. Nunez, Mahmoud S. Alghamri, Ali A. Dabaja, Pedro R. Lowenstein, and Maria G. Castro
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Medicine - Abstract
Epigenetic remodeling is a molecular hallmark of gliomas, and it has been identified as a key mediator of glioma progression. Epigenetic dysregulation contributes to gliomagenesis, tumor progression, and responses to immunotherapies, as well as determining clinical features. This epigenetic remodeling includes changes in histone modifications, chromatin structure, and DNA methylation, all of which are driven by mutations in genes such as histone 3 genes (H3C1 and H3F3A), isocitrate dehydrogenase 1/2 (IDH1/2), α-thalassemia/mental retardation, X-linked (ATRX), and additional chromatin remodelers. Although much of the initial research primarily identified how the epigenetic aberrations impacted glioma progression by solely examining the glioma cells, recent studies have aimed at establishing the role of epigenetic alterations in shaping the tumor microenvironment (TME). In this review, we discuss the mechanisms by which these epigenetic phenomena in glioma remodel the TME and how current therapies targeting epigenetic dysregulation affect the glioma immune response and therapeutic outcomes. Understanding the link between epigenetic remodeling and the glioma TME provides insights into the implementation of epigenetic-targeting therapies to improve the antitumor immune response.
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- 2023
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3. H3.3-G34 mutations impair DNA repair and promote cGAS/STING-mediated immune responses in pediatric high-grade glioma models
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Santiago Haase, Kaushik Banerjee, Anzar A. Mujeeb, Carson S. Hartlage, Fernando M. Núñez, Felipe J. Núñez, Mahmoud S. Alghamri, Padma Kadiyala, Stephen Carney, Marcus N. Barissi, Ayman W. Taher, Emily K. Brumley, Sarah Thompson, Justin T. Dreyer, Caitlin T. Alindogan, Maria B. Garcia-Fabiani, Andrea Comba, Sriram Venneti, Visweswaran Ravikumar, Carl Koschmann, Ángel M. Carcaboso, Maria Vinci, Arvind Rao, Jennifer S. Yu, Pedro R. Lowenstein, and Maria G. Castro
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Oncology ,Therapeutics ,Medicine - Abstract
Pediatric high-grade gliomas (pHGGs) are the leading cause of cancer-related deaths in children in the USA. Sixteen percent of hemispheric pediatric and young adult HGGs encode Gly34Arg/Val substitutions in the histone H3.3 (H3.3-G34R/V). The mechanisms by which H3.3-G34R/V drive malignancy and therapeutic resistance in pHGGs remain unknown. Using a syngeneic, genetically engineered mouse model (GEMM) and human pHGG cells encoding H3.3-G34R, we demonstrate that this mutation led to the downregulation of DNA repair pathways. This resulted in enhanced susceptibility to DNA damage and inhibition of the DNA damage response (DDR). We demonstrate that genetic instability resulting from improper DNA repair in G34R-mutant pHGG led to the accumulation of extrachromosomal DNA, which activated the cyclic GMP–AMP synthase/stimulator of IFN genes (cGAS/STING) pathway, inducing the release of immune-stimulatory cytokines. We treated H3.3-G34R pHGG–bearing mice with a combination of radiotherapy (RT) and DNA damage response inhibitors (DDRi) (i.e., the blood-brain barrier–permeable PARP inhibitor pamiparib and the cell-cycle checkpoint CHK1/2 inhibitor AZD7762), and these combinations resulted in long-term survival for approximately 50% of the mice. Moreover, the addition of a STING agonist (diABZl) enhanced the therapeutic efficacy of these treatments. Long-term survivors developed immunological memory, preventing pHGG growth upon rechallenge. These results demonstrate that DDRi and STING agonists in combination with RT induced immune-mediated therapeutic efficacy in G34-mutant pHGG.
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- 2022
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4. Murine brain tumor microenvironment immunophenotyping using mass cytometry
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Brandon L. McClellan, Mahmoud S. Alghamri, Rohit Thalla, Pedro R. Lowenstein, and Maria G. Castro
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Antibody ,Cancer ,Cell Biology ,Flow Cytometry/Mass Cytometry ,Immunology ,Model Organisms ,Science (General) ,Q1-390 - Abstract
Summary: Here, we present a mass cytometry protocol optimized to examine the phenotype of immune cells within the mouse glioma microenvironment, using a Sleeping Beauty transposon-mediated mouse glioma model. We describe antibody conjugation and titrations for analysis of immune cells. We then detail mouse brain tumor tissue collection and processing, staining, followed by data acquisition, analysis, and gating strategy. This protocol can be applied to any brain tumor-harboring mouse model.For complete details on the use and execution of this protocol, please refer to Alghamri et al. (2021).
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- 2022
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5. Genetic Alterations in Gliomas Remodel the Tumor Immune Microenvironment and Impact Immune-Mediated Therapies
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Maria B. Garcia-Fabiani, Santiago Haase, Andrea Comba, Stephen Carney, Brandon McClellan, Kaushik Banerjee, Mahmoud S. Alghamri, Faisal Syed, Padma Kadiyala, Felipe J. Nunez, Marianela Candolfi, Antonela Asad, Nazareno Gonzalez, Marisa E. Aikins, Anna Schwendeman, James J. Moon, Pedro R. Lowenstein, and Maria G. Castro
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glioma ,immune microenviroment ,immunotherapy ,mouse model ,clinical trial ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
High grade gliomas are malignant brain tumors that arise in the central nervous system, in patients of all ages. Currently, the standard of care, entailing surgery and chemo radiation, exhibits a survival rate of 14-17 months. Thus, there is an urgent need to develop new therapeutic strategies for these malignant brain tumors. Currently, immunotherapies represent an appealing approach to treat malignant gliomas, as the pre-clinical data has been encouraging. However, the translation of the discoveries from the bench to the bedside has not been as successful as with other types of cancer, and no long-lasting clinical benefits have been observed for glioma patients treated with immune-mediated therapies so far. This review aims to discuss our current knowledge about gliomas, their molecular particularities and the impact on the tumor immune microenvironment. Also, we discuss several murine models used to study these therapies pre-clinically and how the model selection can impact the outcomes of the approaches to be tested. Finally, we present different immunotherapy strategies being employed in clinical trials for glioma and the newest developments intended to harness the immune system against these incurable brain tumors.
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- 2021
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6. Targeting Neuroinflammation in Brain Cancer: Uncovering Mechanisms, Pharmacological Targets, and Neuropharmaceutical Developments
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Mahmoud S. Alghamri, Brandon L. McClellan, Carson S. Hartlage, Santiago Haase, Syed Mohd Faisal, Rohit Thalla, Ali Dabaja, Kaushik Banerjee, Stephen V. Carney, Anzar A. Mujeeb, Michael R. Olin, James J. Moon, Anna Schwendeman, Pedro R. Lowenstein, and Maria G. Castro
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immunosuppression ,inflammation ,tumor microenvironment ,glioma ,immunotherapy ,Therapeutics. Pharmacology ,RM1-950 - Abstract
Gliomas are one of the most lethal types of cancers accounting for ∼80% of all central nervous system (CNS) primary malignancies. Among gliomas, glioblastomas (GBM) are the most aggressive, characterized by a median patient survival of fewer than 15 months. Recent molecular characterization studies uncovered the genetic signatures and methylation status of gliomas and correlate these with clinical prognosis. The most relevant molecular characteristics for the new glioma classification are IDH mutation, chromosome 1p/19q deletion, histone mutations, and other genetic parameters such as ATRX loss, TP53, and TERT mutations, as well as DNA methylation levels. Similar to other solid tumors, glioma progression is impacted by the complex interactions between the tumor cells and immune cells within the tumor microenvironment. The immune system’s response to cancer can impact the glioma’s survival, proliferation, and invasiveness. Salient characteristics of gliomas include enhanced vascularization, stimulation of a hypoxic tumor microenvironment, increased oxidative stress, and an immune suppressive milieu. These processes promote the neuro-inflammatory tumor microenvironment which can lead to the loss of blood-brain barrier (BBB) integrity. The consequences of a compromised BBB are deleteriously exposing the brain to potentially harmful concentrations of substances from the peripheral circulation, adversely affecting neuronal signaling, and abnormal immune cell infiltration; all of which can lead to disruption of brain homeostasis. In this review, we first describe the unique features of inflammation in CNS tumors. We then discuss the mechanisms of tumor-initiating neuro-inflammatory microenvironment and its impact on tumor invasion and progression. Finally, we also discuss potential pharmacological interventions that can be used to target neuro-inflammation in gliomas.
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- 2021
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7. Current Approaches for Glioma Gene Therapy and Virotherapy
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Kaushik Banerjee, Felipe J. Núñez, Santiago Haase, Brandon L. McClellan, Syed M. Faisal, Stephen V. Carney, Jin Yu, Mahmoud S. Alghamri, Antonela S. Asad, Alejandro J. Nicola Candia, Maria Luisa Varela, Marianela Candolfi, Pedro R. Lowenstein, and Maria G. Castro
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gene therapy ,glioma ,viral vectors ,non-viral vectors ,HSV1-TK ,mutant IDH1 3 ,Neurosciences. Biological psychiatry. Neuropsychiatry ,RC321-571 - Abstract
Glioblastoma (GBM) is the most common and aggressive primary brain tumor in the adult population and it carries a dismal prognosis. Inefficient drug delivery across the blood brain barrier (BBB), an immunosuppressive tumor microenvironment (TME) and development of drug resistance are key barriers to successful glioma treatment. Since gliomas occur through sequential acquisition of genetic alterations, gene therapy, which enables to modification of the genetic make-up of target cells, appears to be a promising approach to overcome the obstacles encountered by current therapeutic strategies. Gene therapy is a rapidly evolving field with the ultimate goal of achieving specific delivery of therapeutic molecules using either viral or non-viral delivery vehicles. Gene therapy can also be used to enhance immune responses to tumor antigens, reprogram the TME aiming at blocking glioma-mediated immunosuppression and normalize angiogenesis. Nano-particles-mediated gene therapy is currently being developed to overcome the BBB for glioma treatment. Another approach to enhance the anti-glioma efficacy is the implementation of viro-immunotherapy using oncolytic viruses, which are immunogenic. Oncolytic viruses kill tumor cells due to cancer cell-specific viral replication, and can also initiate an anti-tumor immunity. However, concerns still remain related to off target effects, and therapeutic and transduction efficiency. In this review, we describe the rationale and strategies as well as advantages and disadvantages of current gene therapy approaches against gliomas in clinical and preclinical studies. This includes different delivery systems comprising of viral, and non-viral delivery platforms along with suicide/prodrug, oncolytic, cytokine, and tumor suppressor-mediated gene therapy approaches. In addition, advances in glioma treatment through BBB-disruptive gene therapy and anti-EGFRvIII/VEGFR gene therapy are also discussed. Finally, we discuss the results of gene therapy-mediated human clinical trials for gliomas. In summary, we highlight the progress, prospects and remaining challenges of gene therapies aiming at broadening our understanding and highlighting the therapeutic arsenal for GBM.
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- 2021
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8. A novel miR1983-TLR7-IFNβ circuit licenses NK cells to kill glioma cells, and is under the control of galectin-1
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Diana Shah, Andrea Comba, Syed M. Faisal, Padma Kadiyala, Gregory J. Baker, Mahmoud S. Alghamri, Robert Doherty, Daniel Zamler, Gabriel Nuñez, Maria G. Castro, and Pedro R. Lowenstein
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glioblastoma ,galectin-1 ,nk cells ,tlr7 ,myd88 ,irf5 ,irf7 ,ifn-β ,mir-1983 ,Immunologic diseases. Allergy ,RC581-607 ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Although pharmacological stimulation of TLRs has anti-tumor effects, it has not been determined whether endogenous stimulation of TLRs can lead to tumor rejection. Herein, we demonstrate the existence of an innate anti-glioma NK-mediated circuit initiated by glioma-released miR-1983 within exosomes, and which is under the regulation of galectin-1 (Gal-1). We demonstrate that miR-1983 is an endogenous TLR7 ligand that activates TLR7 in pDCs and cDCs through a 5ʹ-UGUUU-3ʹ motif at its 3ʹ end. TLR7 activation and downstream signaling through MyD88-IRF5/IRF7 stimulates secretion of IFN-β. IFN-β then stimulates NK cells resulting in the eradication of gliomas. We propose that successful immunotherapy for glioma could exploit this endogenous innate immune circuit to activate TLR7 signaling and stimulate powerful anti-glioma NK activity, at least 10–14 days before the activation of anti-tumor adaptive immunity.
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- 2021
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9. The Coxsackievirus and Adenovirus Receptor Has a Short Half-Life in Epithelial Cells
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Poornima Kotha Lakshmi Narayan, James M. Readler, Mahmoud S. Alghamri, Trisha L. Brockman, Ran Yan, Priyanka Sharma, Vladislav Snitsarev, Katherine J. D. A. Excoffon, and Abimbola O. Kolawole
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human adenovirus ,coxsackievirus and adenovirus receptor ,half-life ,polarized epithelia ,Medicine - Abstract
The coxsackievirus and adenovirus receptor (CAR) is an essential cellular protein that is involved in cell adhesion, cell signaling, and viral infection. The 8-exon encoded isoform (CAREx8) resides at the apical surface of polarized epithelia, where it is accessible as a receptor for adenovirus entering the airway lumen. Given its pivotal role in viral infection, it is a target for antiviral strategies. To understand the regulation of CAREx8 and determine the feasibility of receptor downregulation, the half-life of total and apical localized CAREx8 was determined and correlated with adenovirus transduction. Total and apical CAREx8 has a relatively short half-life of approximately 2 h. The half-life of apical CAREx8 correlates well with adenovirus transduction. These results suggest that antiviral strategies that aim to degrade the primary receptor for apical adenovirus infection will be effective within a relatively short time frame after application.
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- 2022
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10. Melanoma induced immunosuppression is mediated by hematopoietic dysregulation
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Neha Kamran, Youping Li, Maria Sierra, Mahmoud S. Alghamri, Padma Kadiyala, Henry D. Appelman, Marta Edwards, Pedro R. Lowenstein, and Maria G. Castro
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immunosuppressive ,myeloid derived suppressor cells ,tumor microenvironment ,tumor associated macrophages ,Immunologic diseases. Allergy ,RC581-607 ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Tumors are associated with expansion of immunosuppressive cells such as tumor associated macrophages (TAMs), regulatory T cells (Tregs) and myeloid derived suppressor cells (MDSCs). These cells promote tumor growth, angiogenesis, metastasis and immune escape. Cancer patients frequently present symptoms such as anemia, leukocytosis and/or cytopenia; associated with poor prognosis. To uncover tumor-mediated hematopoietic abnormalities and identify novel targets that can be harnessed to improve tumor-specific immune responses, we investigated the hematopoietic stem and progenitor cell compartment in melanoma bearing mice. We show that melanoma growth results in expansion of myeloid lineages such as MDSCs, macrophages and DCs along with a reduction in mature RBCs and platelets. Mature B lymphocytes in the blood and BM of melanoma mice were also reduced. Mice bearing melanoma showed extramedullary hematopoiesis in the spleen. Increased expansion of myeloid lineages occurred directly at the level of stem and progenitor cells. The reduction in mature B lymphocytes resulted from a block at the Pro-B cell stage in the bone marrow. Addition of recombinant IL-3 to bone marrow cells resulted in the expansion of committed myeloid progenitors including common myeloid precursors, granulocyte-monocyte precursors and megakaryocyte-erythrocyte precursors. In vivo, IL-3 receptor stimulation in melanoma bearing mice using an IL-3 antibody also resulted in a robust expansion of committed myeloid progenitors and hematopoietic stem cells. Collectively our findings demonstrate that tumor growth plays a pivotal role in reprogramming the host immune system by impacting hematopoiesis directly at the level of stem cell compartment.
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- 2018
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11. The magic of MAGI‐1: A scaffolding protein with multi signalosomes and functional plasticity
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Katherine J. D. A. Excoffon, Christina L. Avila, Mahmoud S. Alghamri, and Abimbola O. Kolawole
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Humans ,PDZ Domains ,Cell Biology ,General Medicine - Abstract
MAGI-1 is a critical cellular scaffolding protein with over 110 different cellular and microbial protein interactors. Since the discovery of MAGI-1 in 1997, MAGI-1 has been implicated in diverse cellular functions such as polarity, cell-cell communication, neurological processes, kidney function, and a host of diseases including cancer and microbial infection. Additionally, MAGI-1 has undergone nomenclature changes in response to the discovery of an additional PDZ domain, leading to lack of continuity in the literature. We address the nomenclature of MAGI-1 as well as summarize many of the critical functions of the known interactions. Given the importance of many of the interactors, such as human papillomavirus E6, the Coxsackievirus and adenovirus receptor (CAR), and PTEN, the enhancement or disruption of MAGI-based interactions has the potential to affect cellular functions that can potentially be harnessed as a therapeutic strategy for a variety of diseases.
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- 2022
12. T lymphocytes as dynamic regulators of glioma pathobiology
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Elizabeth C Cordell, Mahmoud S Alghamri, Maria G Castro, and David H Gutmann
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Cancer Research ,Oncology ,Neurology (clinical) - Abstract
The brain tumor microenvironment contains numerous distinct types of nonneoplastic cells, which each serve a diverse set of roles relevant to the formation, maintenance, and progression of these central nervous system cancers. While varying in frequencies, monocytes (macrophages, microglia, and myeloid-derived suppressor cells), dendritic cells, natural killer cells, and T lymphocytes represent the most common nonneoplastic cellular constituents in low- and high-grade gliomas (astrocytomas). Although T cells are conventionally thought to target and eliminate neoplastic cells, T cells also exist in other states, characterized by tolerance, ignorance, anergy, and exhaustion. In addition, T cells can function as drivers of brain cancer growth, especially in low-grade gliomas. Since T cells originate in the blood and bone marrow sinuses, their capacity to function as both positive and negative regulators of glioma growth has ignited renewed interest in their deployment as immunotherapeutic agents. In this review, we discuss the roles of T cells in low- and high-grade glioma formation and progression, as well as the potential uses of modified T lymphocytes for brain cancer therapeutics.
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- 2022
13. Systemic delivery of an adjuvant CXCR4-CXCL12 signaling inhibitor encapsulated in synthetic protein nanoparticles for glioma immunotherapy
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Mahmoud S. Alghamri, Kaushik Banerjee, Anzar A. Mujeeb, Ava Mauser, Ayman Taher, Rohit Thalla, Brandon L. McClellan, Maria L. Varela, Svetlana M. Stamatovic, Gabriela Martinez-Revollar, Anuska V. Andjelkovic, Jason V. Gregory, Padma Kadiyala, Alexandra Calinescu, Jennifer A. Jiménez, April A. Apfelbaum, Elizabeth R. Lawlor, Stephen Carney, Andrea Comba, Syed Mohd Faisal, Marcus Barissi, Marta B. Edwards, Henry Appelman, Yilun Sun, Jingyao Gan, Rose Ackermann, Anna Schwendeman, Marianela Candolfi, Michael R. Olin, Joerg Lahann, Pedro R. Lowenstein, and Maria G. Castro
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Receptors, CXCR4 ,General Engineering ,General Physics and Astronomy ,Glioma ,Article ,Chemokine CXCL12 ,Mice ,Cell Line, Tumor ,Tumor Microenvironment ,Animals ,Humans ,Nanoparticles ,General Materials Science ,Immunotherapy ,Glioblastoma ,Cell Proliferation ,Signal Transduction - Abstract
Glioblastoma (GBM) is an aggressive primary brain cancer; with a 5-year survival of ~5%. Challenges that hamper GBM therapeutic efficacy include: (i) tumor heterogeneity, (ii) treatment resistance, (iii) immunosuppressive tumor microenvironment (TME) and (iv) the blood-brain barrier (BBB). The C-X-C Motif Chemokine Ligand-12/ C-X-C Motif Chemokine Receptor-4 (CXCL12/CXCR4) signaling pathway is activated in GBM and is associated with tumor progression. Although the CXCR4 antagonist (AMD3100) has been proposed as an attractive anti-GBM therapeutic target, it’s poor pharmacokinetic properties, and unfavorable bioavailability have hampered its clinical implementation. Thus, we developed synthetic protein nanoparticles (SPNPs) coated with the transcytotic peptide iRGD (AMD3100-SPNPs) to target the CXCL2/CXCR4 pathway in GBM via systemic delivery. We showed that AMD3100-SPNPs block CXCL12/CXCR4 signaling in three mouse and human GBM cell cultures in vitro and in a GBM mouse model in vivo. This results in (i) inhibition of GBM proliferation, (ii) reduced infiltration of CXCR4(+) monocytic myeloid derived suppressor cells (M-MDSCs) into the TME, (iii) restoration of BBB integrity, and (iv) induction of immunogenic cell death (ICD), sensitizing the tumor to radiotherapy, and leading to anti-GBM immunity. Additionally, we showed that combining AMD3100-SPNPs with radiation led to long term survival; with ~60% of GBM tumor bearing mice remaining tumor free, after rechallenging with a second GBM in the contralateral hemisphere. This was due to a sustained anti-GBM immunological memory response that prevented tumor recurrence without additional treatment. In view of the potent ICD induction and reprogrammed tumor microenvironment, this SPNP-mediated strategy has a significant clinical translation applicability.
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- 2022
14. G-CSF secreted by mutant IDH1 glioma stem cells abolishes myeloid cell immunosuppression and enhances the efficacy of immunotherapy
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Karen Eddy, Maria B. Garcia-Fabiani, Ruthvik Avvari, Ayman Taher, Brandon L. McClellan, Dolores Hambardzumyan, Maria Ventosa, Joshua D. Welch, Sofia D. Merajver, Syed M Faisal, Wajd N. Al-Holou, Maria G. Castro, Santiago Haase, Jason Heth, Chao Gao, Parag G. Patil, Felipe J Nunez, Rohit Thalla, Mahmoud S. Alghamri, Margaret S. Hartlage, Li Zhang, Gabriel Núñez, Shawn L. Hervey-Jumper, Pedro R. Lowenstein, Neha Kamran, Peter J. Ulintz, Jialin Liu, Daniel A. Orringer, and Stephen Carney
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Tumor microenvironment ,Multidisciplinary ,Myeloid ,Genetic enhancement ,Immunology ,SciAdv r-articles ,Life Sciences ,Cell Biology ,Biology ,medicine.disease ,medicine.anatomical_structure ,Tumor progression ,Glioma ,medicine ,Cancer research ,Bone marrow ,Biomedicine and Life Sciences ,Stem cell ,Reprogramming ,Research Article - Abstract
Description, Mutant IDH1 gliomas are infiltrated by nonsuppressive immature myeloid cells, resulting in enhanced response to immunotherapy., Mutant isocitrate-dehydrogenase 1 (mIDH1) synthesizes the oncometabolite 2-hydroxyglutarate (2HG), which elicits epigenetic reprogramming of the glioma cells’ transcriptome by inhibiting DNA and histone demethylases. We show that the efficacy of immune-stimulatory gene therapy (TK/Flt3L) is enhanced in mIDH1 gliomas, due to the reprogramming of the myeloid cells’ compartment infiltrating the tumor microenvironment (TME). We uncovered that the immature myeloid cells infiltrating the mIDH1 TME are mainly nonsuppressive neutrophils and preneutrophils. Myeloid cell reprogramming was triggered by granulocyte colony-stimulating factor (G-CSF) secreted by mIDH1 glioma stem/progenitor-like cells. Blocking G-CSF in mIDH1 glioma–bearing mice restores the inhibitory potential of the tumor-infiltrating myeloid cells, accelerating tumor progression. We demonstrate that G-CSF reprograms bone marrow granulopoiesis, resulting in noninhibitory myeloid cells within mIDH1 glioma TME and enhancing the efficacy of immune-stimulatory gene therapy.
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- 2021
15. Systemic delivery of a CXCR4-CXCL12 signaling inhibitor encapsulated in synthetic protein nanoparticles for glioma immunotherapy
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Alexandra Calinescu, Rohit Thalla, Mahmoud S. Alghamri, Jennifer A. Jiménez, Maria Luisa Varela, Marta Edwards, Jason V. Gregory, Marcus Barissi, Padma Kadiyala, April A. Apfelbaum, Gabriela Martinez-Revollar, Pedro R. Lowenstein, Andrea Comba, Stephen Carney, Anzar A. Mujeeb, Maria G. Castro, Joerg Lahann, Svetlana M. Stamatovic, Ayman Taher, Brandon L. McClellan, Michael R. Olin, Syed M Faisal, Anuska Andjelkovic-Zochowska, Kaushik Banerjee, Elizabeth R Lawlor, and Henry D. Appelman
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Chemokine ,Tumor microenvironment ,Myeloid ,biology ,Chemistry ,medicine.medical_treatment ,Immunotherapy ,medicine.disease ,CXCR4 ,medicine.anatomical_structure ,Immune system ,Glioma ,biology.protein ,medicine ,Cancer research ,Cytotoxic T cell - Abstract
Glioblastoma multiforme (GBM) is an aggressive primary brain tumor, with poor prognosis. Major obstacles hampering effective therapeutic response in GBM are tumor heterogeneity, high infiltration of immunosuppressive myeloid cells, and the presence of the blood-brain barrier. The C-X-C Motif Chemokine Ligand 12/ C-X-C Motif Chemokine Receptor 4 (CXCL12/ CXCR4) signaling pathway is implicated in GBM invasion and cell cycle progression. While the CXCR4 antagonists (AMD3100) has a potential anti-GBM effects, its poor pharmacokinetic and systemic toxicity had precluded its clinical application. Moreover, the role of CXCL12/ CXCR4 signaling pathway in anti-GBM immunity, particularly in GBM-mediated immunosuppression has not been elucidated. Here, we developed a synthetic protein nanoparticle (SPNPs) coated with the cell-penetrating peptide iRGD (AMD3100 SPNPs) to target the CXCR4/CXCL12 signaling axis in GBM. We showed that AMD3100 SPNPs effectively blocked CXCR4 signaling in mouse and human GBM cells in vitro as well as in GBM model in vivo. This results in inhibition of GBM proliferation and induction of immunogenic tumor cell death (ICD) leading to inhibition of GBM progression. Our data also demonstrate that blocking CXCR4 sensitizes GBM cells to radiation, eliciting enhanced release of ICD ligands. Combining AMD3100 SPNPs with radiotherapy inhibited GBM progression and led to long-term survival; with 60% of mice remaining tumor-free. This was accompanied by an anti-GBM immune response and sustained immunological memory that prevented tumor recurrence without further treatment. Finally, we showed that systemic delivery of AMD3100 SPNPs decreased the infiltration of CXCR4+ monocytic myeloid-derived suppressor cells to the tumor microenvironment. With the potent ICD induction and reprogrammed immune microenvironment, this strategy has significant potential for future clinical translation.Graphical abstractImmunological mechanism targeting Glioblastoma (GBM) upon blocking CXCR4 signaling pathway with AMD3100-conjugated nanoparticles (SPNPs).(1) Radiotherapy induces glioma cell death, followed by Damage-associated molecular patterns (DAMPs) release. Dendritic cells (DC) are activated by DAMPs and migrate to the regional lymph node where they prime cytotoxic T lymphocyte immune response. Tumor-specific cytotoxic T cells infiltrate the tumor and attack glioma cells. (2) Glioma cells express CXCR4, as well its ligand CXCL12. CXCL12 induces glioma cell proliferation and, (3) as well as mobilization in the bone marrow of CXCR4 expressing myeloid MDSC, which will infiltrate the tumor, and inhibit tumor-specific cytotoxic T cells activity. GEMM of glioma when treated systemically with SPNPs AMD3100 SPNPs plus radiation, nanoparticles block the interaction between CXCR4 and CXCL12, thus (4) inhibiting glioma cell proliferation and (5) reducing mobilization in the bone marrow of CXCR4 expressing myeloid MDSC, (6) generating a reduced MDSC tumor infiltration, as well as releasing MDSC inhibition over tumor specific cytotoxic T cell response.
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- 2021
16. A novel miR1983-TLR7-IFNβ circuit licenses NK cells to kill glioma cells, and is under the control of galectin-1
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Gabriel Núñez, Robert Doherty, Padma Kadiyala, Maria G. Castro, Diana Shah, Syed M Faisal, Daniel Zamler, Andrea Comba, Pedro R. Lowenstein, Gregory J. Baker, and Mahmoud S. Alghamri
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Galectin 1 ,medicine.medical_treatment ,Immunology ,Endogeny ,NK cells ,Biology ,Glioma ,IRF5 ,medicine ,IRF7 ,Immunology and Allergy ,Humans ,galectin-1 ,miR-1983 ,RC254-282 ,IFN-β ,Original Research ,TLR7 ,Innate immune system ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,virus diseases ,Immunotherapy ,Interferon-beta ,RC581-607 ,medicine.disease ,Acquired immune system ,MyD88 ,Microvesicles ,Cell biology ,Killer Cells, Natural ,MicroRNAs ,Oncology ,Toll-Like Receptor 7 ,Galectin-1 ,Interferon Regulatory Factors ,Immunologic diseases. Allergy ,Glioblastoma ,Licensure ,Research Article - Abstract
Although pharmacological stimulation of TLRs has anti-tumor effects, it has not been determined whether endogenous stimulation of TLRs can lead to tumor rejection. Herein, we demonstrate the existence of an innate anti-glioma NK-mediated circuit initiated by glioma-released miR-1983 within exosomes, and which is under the regulation of galectin-1 (Gal-1). We demonstrate that miR-1983 is an endogenous TLR7 ligand that activates TLR7 in pDCs and cDCs through a 5ʹ-UGUUU-3ʹ motif at its 3ʹ end. TLR7 activation and downstream signaling through MyD88-IRF5/IRF7 stimulates secretion of IFN-β. IFN-β then stimulates NK cells resulting in the eradication of gliomas. We propose that successful immunotherapy for glioma could exploit this endogenous innate immune circuit to activate TLR7 signaling and stimulate powerful anti-glioma NK activity, at least 10–14 days before the activation of anti-tumor adaptive immunity.
- Published
- 2021
17. MAGI-1 PDZ2 Domain Blockade Averts Adenovirus Infection via Enhanced Proteolysis of the Apical Coxsackievirus and Adenovirus Receptor
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S. Dean Rider, Katherine J. D. A. Excoffon, Mahmoud S. Alghamri, Timothy L. Williamson, Abimbola O. Kolawole, Heather A. Hostetler, Priyanka Sharma, James M. Readler, Ran Yan, and David R. Cool
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endocrine system ,Coxsackie and Adenovirus Receptor-Like Membrane Protein ,viruses ,Adenoviridae Infections ,Immunology ,PDZ domain ,Coxsackievirus ,ADAM17 Protein ,01 natural sciences ,Microbiology ,Regulated Intramembrane Proteolysis ,Adenoviridae ,Madin Darby Canine Kidney Cells ,03 medical and health sciences ,Transduction (genetics) ,Mice ,Dogs ,Protein Domains ,Virology ,medicine ,Animals ,Humans ,Adenovirus infection ,Receptor ,030304 developmental biology ,Adaptor Proteins, Signal Transducing ,0303 health sciences ,biology ,010405 organic chemistry ,virus diseases ,3T3 Cells ,biology.organism_classification ,medicine.disease ,0104 chemical sciences ,Cell biology ,Virus-Cell Interactions ,HEK293 Cells ,Insect Science ,Cell-penetrating peptide ,Amyloid Precursor Protein Secretases ,Cell Adhesion Molecules ,Guanylate Kinases ,Binding domain - Abstract
Adenoviruses (AdVs) are etiological agents of gastrointestinal, heart, eye, and respiratory tract infections that can be lethal for immunosuppressed people. Many AdVs use the coxsackievirus and adenovirus receptor (CAR) as a primary receptor. The CAR isoform resulting from alternative splicing that includes the eighth exon, CAR(Ex8), localizes to the apical surface of polarized epithelial cells and is responsible for the initiation of AdV infection. We have shown that the membrane level of CAR(Ex8) is tightly regulated by two MAGI-1 PDZ domains, PDZ2 and PDZ4, resulting in increased or decreased AdV transduction, respectively. We hypothesized that targeting the interactions between the MAGI-1 PDZ2 domain and CAR(Ex8) would decrease the apical CAR(Ex8) expression level and prevent AdV infection. Decoy peptides that target MAGI-1 PDZ2 were synthesized (TAT-E6 and TAT-NET1). PDZ2 binding peptides decreased CAR(Ex8) expression and reduced AdV transduction. CAR(Ex8) degradation was triggered by the activation of the regulated intramembrane proteolysis (RIP) pathway through a disintegrin and metalloproteinase (ADAM17) and γ-secretase. Further analysis revealed that ADAM17 interacts directly with the MAGI-1 PDZ3 domain, and blocking the PDZ2 domain enhanced the accessibility of ADAM17 to the substrate (CAR(Ex8)). Finally, we validated the efficacy of TAT-PDZ2 peptides in protecting the epithelia from AdV transduction in vivo using a novel transgenic animal model. Our data suggest that TAT-PDZ2 binding peptides are novel anti-AdV molecules that act by enhanced RIP of CAR(Ex8) and decreased AdV entry. This strategy has additional translational potential for targeting other viral receptors that have PDZ binding domains, such as the angiotensin-converting enzyme 2 receptor. IMPORTANCE Adenovirus is a common threat in immunosuppressed populations and military recruits. There are no currently approved treatments/prophylactic agents that protect from most AdV infections. Here, we developed peptide-based small molecules that can suppress AdV infection of polarized epithelia by targeting the AdV receptor, coxsackievirus and adenovirus receptor (CAR(Ex8)). The newly discovered peptides target a specific PDZ domain of the CAR(Ex8)-interacting protein MAGI-1 and decrease AdV transduction in multiple polarized epithelial models. Peptide-induced CAR(Ex8) degradation is triggered by extracellular domain (ECD) shedding through ADAM17 followed by γ-secretase-mediated nuclear translocation of the C-terminal domain. The enhanced shedding of the CAR(Ex8) ECD further protected the epithelium from AdV infection. Taken together, these novel molecules protect the epithelium from AdV infection. This approach may be applicable to the development of novel antiviral molecules against other viruses that use a receptor with a PDZ binding domain.
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- 2021
18. Current Approaches for Glioma Gene Therapy and Virotherapy
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Kaushik Banerjee, Felipe J. Núñez, Santiago Haase, Brandon L. McClellan, Syed M. Faisal, Stephen V. Carney, Jin Yu, Mahmoud S. Alghamri, Antonela S. Asad, Alejandro J. Nicola Candia, Maria Luisa Varela, Marianela Candolfi, Pedro R. Lowenstein, and Maria G. Castro
- Subjects
0301 basic medicine ,viral vectors ,Genetic enhancement ,medicine.medical_treatment ,mutant IDH1 3 ,Review ,Viral vector ,lcsh:RC321-571 ,03 medical and health sciences ,Cellular and Molecular Neuroscience ,0302 clinical medicine ,HSV1-TK ,Glioma ,glioma ,non-viral vectors ,Medicine ,Virotherapy ,Molecular Biology ,lcsh:Neurosciences. Biological psychiatry. Neuropsychiatry ,FMS-like tyrosine kinase 3 ligand ,Tumor microenvironment ,business.industry ,Immunotherapy ,medicine.disease ,gene therapy ,Oncolytic virus ,030104 developmental biology ,030220 oncology & carcinogenesis ,Drug delivery ,Cancer research ,immunotherapy ,business ,Neuroscience - Abstract
Glioblastoma (GBM) is the most common and aggressive primary brain tumor in the adult population and it carries a dismal prognosis. Inefficient drug delivery across the blood brain barrier (BBB), an immunosuppressive tumor microenvironment (TME) and development of drug resistance are key barriers to successful glioma treatment. Since gliomas occur through sequential acquisition of genetic alterations, gene therapy, which enables to modification of the genetic make-up of target cells, appears to be a promising approach to overcome the obstacles encountered by current therapeutic strategies. Gene therapy is a rapidly evolving field with the ultimate goal of achieving specific delivery of therapeutic molecules using either viral or non-viral delivery vehicles. Gene therapy can also be used to enhance immune responses to tumor antigens, reprogram the TME aiming at blocking glioma-mediated immunosuppression and normalize angiogenesis. Nano-particles-mediated gene therapy is currently being developed to overcome the BBB for glioma treatment. Another approach to enhance the anti-glioma efficacy is the implementation of viro-immunotherapy using oncolytic viruses, which are immunogenic. Oncolytic viruses kill tumor cells due to cancer cell-specific viral replication, and can also initiate an anti-tumor immunity. However, concerns still remain related to off target effects, and therapeutic and transduction efficiency. In this review, we describe the rationale and strategies as well as advantages and disadvantages of current gene therapy approaches against gliomas in clinical and preclinical studies. This includes different delivery systems comprising of viral, and non-viral delivery platforms along with suicide/prodrug, oncolytic, cytokine, and tumor suppressor-mediated gene therapy approaches. In addition, advances in glioma treatment through BBB-disruptive gene therapy and anti-EGFRvIII/VEGFR gene therapy are also discussed. Finally, we discuss the results of gene therapy-mediated human clinical trials for gliomas. In summary, we highlight the progress, prospects and remaining challenges of gene therapies aiming at broadening our understanding and highlighting the therapeutic arsenal for GBM.
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- 2020
19. G-CSF Secreted by Epigenetically Reprogrammed Mutant IDH1 Glioma Stem Cells Reverses the Myeloid Cells’-Mediated Immunosuppressive Tumor Microenvironment
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Santiago Haase, Karen Eddy, Felipe J Nunez, Chao Gao, Ruthvik Avvari, Parag G. Patil, Maria G. Castro, Pedro R. Lowenstein, Syed M Faisal, Peter J. Ulintz, Dolores Hambardzumyan, Jason Heth, Gabriel Núñez, Stephen Carney, Shawn L. Hervey-Jumper, Neha Kamran, Joshua D. Welch, Jialin Liu, Daniel A. Orringer, Sophia Merajver, Rohit Thalla, Mahmoud S. Alghamri, Li Zhang, Maria B. Garcia-Fabiani, Maria Ventosa, Ayman Taher, and Wajd N. Al-Holou
- Subjects
Tumor microenvironment ,Immune system ,Tumor progression ,Chemistry ,Glioma ,DNA methylation ,medicine ,Cancer research ,Stem cell ,medicine.disease ,Reprogramming ,ATRX - Abstract
Mutation in isocitrate dehydrogenase (mIDH) is a gain of function mutation resulting in the production of the oncometabolite, R-2-hydroxyglutarate, that inhibits DNA and histone demethylases. The resultant hypermethylation phenotype reprograms the glioma cells’ transcriptome and elicits profound effects on glioma immunity. We report that in mouse models and human gliomas, mIDH1 in the context of ATRX and TP53 inactivation results in global expansion of the granulocytic myeloid cells’ compartment. Single-cell RNA-sequencing coupled with mass cytometry analysis revealed that these granulocytes are mainly non-immunosuppressive neutrophils and pre-neutrophils; with a small fraction of polymorphonuclear myeloid-derived suppressor cells. The mechanism of mIDH1 mediated pre-neutrophils expansion involves epigenetic reprogramming which leads to enhanced expression of the granulocyte colony-stimulating factor (G-CSF). Blocking G-CSF restored the inhibitory potential of PMN-MDSCs and enhanced tumor progression. Thus, G-CSF induces remodeling of the inhibitory PMN-MDSCs in mIDH1 glioma rendering them non-immunosuppressive; and having significant therapeutic implications.SIGNIFICANCEmIDH1 is the most common mutation in gliomas associated with improved prognosis. Gliomas harboring mIDH1, together with ATRX and TP53 inactivation, exhibit higher circulating levels of G-CSF, ensuing the recruitment and expansion of non-suppressive neutrophils, pre-neutrophils and small fraction of PMN-MDSCs to the TME leading to an immune permissive phenotype.
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- 2020
20. Tumor mutational burden predicts survival in patients with low-grade gliomas expressing mutated IDH1
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Rohit Thalla, Mahmoud S. Alghamri, Ali Dabaja, Maria G. Castro, Lili Zhao, Ayman Taher, Ruthvik Avvari, Pedro R. Lowenstein, and Peter J. Ulintz
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IDH ,0301 basic medicine ,Oncology ,medicine.medical_specialty ,tumor mutational burden ,IDH1 ,clinical prognosis ,03 medical and health sciences ,0302 clinical medicine ,glioma ,Glioma ,Internal medicine ,medicine ,Gene ,ATRX ,business.industry ,Astrocytoma ,Cell cycle ,medicine.disease ,DNA-repair prognostic signature ,030104 developmental biology ,Isocitrate dehydrogenase ,030220 oncology & carcinogenesis ,Basic and Translational Investigations ,Oligodendroglioma ,business - Abstract
Background Gliomas are the most common primary brain tumors. High-Grade Gliomas have a median survival (MS) of 18 months, while Low-Grade Gliomas (LGGs) have an MS of approximately 7.3 years. Seventy-six percent of patients with LGG express mutated isocitrate dehydrogenase (mIDH) enzyme. Survival of these patients ranges from 1 to 15 years, and tumor mutational burden ranges from 0.28 to 3.85 somatic mutations/megabase per tumor. We tested the hypothesis that the tumor mutational burden would predict the survival of patients with tumors bearing mIDH. Methods We analyzed the effect of tumor mutational burden on patients’ survival using clinical and genomic data of 1199 glioma patients from The Cancer Genome Atlas and validated our results using the Glioma Longitudinal AnalySiS consortium. Results High tumor mutational burden negatively correlates with the survival of patients with LGG harboring mIDH (P = .005). This effect was significant for both Oligodendroglioma (LGG-mIDH-O; MS = 2379 vs 4459 days in high vs low, respectively; P = .005) and Astrocytoma (LGG-mIDH-A; MS = 2286 vs 4412 days in high vs low respectively; P = .005). There was no differential representation of frequently mutated genes (eg, TP53, ATRX, CIC, and FUBP) in either group. Gene set enrichment analysis revealed an enrichment in Gene Ontologies related to cell cycle, DNA-damage response in high versus low tumor mutational burden. Finally, we identified 6 gene sets that predict survival for LGG-mIDH-A and LGG-mIDH-O. Conclusions we demonstrate that tumor mutational burden is a powerful, robust, and clinically relevant prognostic factor of MS in mIDH patients.
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- 2020
21. Immunotherapy for gliomas: shedding light on progress in preclinical and clinical development
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Stephen Carney, Andrea Comba, Maria B. Garcia-Fabiani, Alejandro Javier Nicola Candia, Ava Mauser, Anna Schwendeman, Maria Ventosa, Marianela Candolfi, Lindsay Scheetz, Pedro R. Lowenstein, Mahmoud S. Alghamri, Padma Kadiyala, James J. Moon, Joerg Lahann, Maria G. Castro, and Syed M Faisal
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0301 basic medicine ,Oncology ,Surgical resection ,medicine.medical_specialty ,CIENCIAS MÉDICAS Y DE LA SALUD ,Standard of care ,Immune checkpoint inhibitors ,medicine.medical_treatment ,Ciencias de la Salud ,DENDRITIC CELLS ,CHECKPOINT INHIBITOR ,03 medical and health sciences ,High morbidity ,purl.org/becyt/ford/3.3 [https] ,0302 clinical medicine ,Internal medicine ,Glioma ,VACCINES ,parasitic diseases ,medicine ,Tumor Microenvironment ,NANOPARTICLES ,Animals ,Humans ,Pharmacology (medical) ,IMMUNOTHERAPY ,CAR T-CELL ,Pharmacology ,Chemotherapy ,IMMUNOSUPPRESSION ,business.industry ,Brain Neoplasms ,Immunosuppression ,General Medicine ,Immunotherapy ,medicine.disease ,Otras Ciencias de la Salud ,Survival Rate ,030104 developmental biology ,ANTIBODY ,030220 oncology & carcinogenesis ,GLIOMA ,VIRUS ,purl.org/becyt/ford/3 [https] ,business - Abstract
Gliomas are infiltrating brain tumors associated with high morbidity and mortality. Current standard of care includes radiation, chemotherapy and surgical resection. Today, survival rates for malignant glioma patients remain dismal and unchanged for decades. The glioma microenvironment is highly immunosuppressive and consequently this has motivated the development of immunotherapies for counteracting this condition, enabling the immune cells within the tumor microenvironment to react against this tumor.Areas covered: The authors discuss immunotherapeutic strategies for glioma in phase-I/II clinical trials and illuminate their mechanisms of action, limitations and key challenges. They also examine promising approaches under preclinical development.Expert opinion: In the last decade there has been an expansion in immune-mediated anti-cancer therapies. In the glioma field, sophisticated strategies have been successfully implemented in preclinical models. Unfortunately, clinical trials have not yet yielded consistent results for glioma patients. This could be attributed to our limited understanding of the complex immune cell infiltration and its interaction with the tumor cells, the selected time for treatment, the combination with other therapies and the route of administration of the agent. Applying these modalities to treat malignant glioma is challenging, but many new alternatives are emerging to by-pass these hurdles. Fil: Garcia Fabiani, Maria Belen. University of Michigan; Estados Unidos. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina Fil: Ventosa, Maria. University of Michigan; Estados Unidos Fil: Comba, Andrea. University of Michigan; Estados Unidos. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina Fil: Candolfi, Marianela. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Biomédicas. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Biomédicas; Argentina Fil: Nicola Candia, Alejandro Javier. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Biomédicas. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Biomédicas; Argentina Fil: Alghamri, Mahmoud S.. University of Michigan; Estados Unidos Fil: Kadiyala, Padma. University of Michigan; Estados Unidos Fil: Carney, Stephen. University of Michigan; Estados Unidos Fil: Faisal, Syed M.. University of Michigan; Estados Unidos Fil: Schwendeman, Anna. University of Michigan; Estados Unidos Fil: Moon, James J.. University of Michigan; Estados Unidos Fil: Scheetz, Lindsay. University of Michigan; Estados Unidos Fil: Lahann, Joerg. University of Michigan; Estados Unidos Fil: Mauser, Ava. University of Michigan; Estados Unidos Fil: Lowenstein, Pedro R.. University of Michigan; Estados Unidos Fil: Castro, Maria Gabriela. University of Michigan; Estados Unidos
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- 2020
22. Inhibition of 2-Hydroxyglutrate Elicits Metabolic-reprograming and Mutant IDH1 Glioma Immunity
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Maria B. Garcia-Fabiani, Stephen Carney, Anna Schwendeman, Minzhi Yu, Fernando M. Nunez, Marta Edwards, Felipe J Nunez, Padma Kadiyala, Maria G. Castro, Dan Li, Pedro R. Lowenstein, James J. Moon, Mahmoud S. Alghamri, Jessica C. Gauss, and Yayuan Liu
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Tumor microenvironment ,Temozolomide ,IDH1 ,business.industry ,medicine.medical_treatment ,Context (language use) ,medicine.disease ,Targeted therapy ,Immune system ,Glioma ,Cancer research ,medicine ,business ,neoplasms ,ATRX ,medicine.drug - Abstract
Mutant isocitrate-dehydrogenase-1 (IDH1-R132H; mIDH1) is a hallmark of adult gliomas. Lower grade mIDH1 gliomas are classified into two molecular subgroups: (i) 1p/19q co-deletion/TERT-promoter mutations or (ii) inactivating mutations in α-thalassemia/mental retardation syndrome X-linked (ATRX) andTP53.This work, relates to the gliomas’ subtype harboring mIDH1,TP53andATRXinactivation. IDH1-R132H is a gain-of-function mutation that converts α-ketoglutarate into 2-hydroxyglutarate (D-2HG). The role of D-2HG within the tumor microenvironment of mIDH1/mATRX/mTP53 gliomas remains unexplored. Inhibition of 2HG, when used as monotherapy or in combination with radiation and temozolomide (IR/TMZ), led to increased median survival (MS) of mIDH1 glioma bearing mice. Also, 2HG inhibition elicited anti-mIDH1 glioma immunological memory. In response to 2HG inhibition, PD-L1 expression levels on mIDH1-glioma cells increased to similar levels as observed in wild-type-IDH1 gliomas. Thus, we combined 2HG inhibition/IR/TMZ with anti-PDL1 immune checkpoint-blockade and observed complete tumor regression in 60% of mIDH1 glioma bearing mice. This combination strategy reduced T-cell exhaustion and favored the generation of memory CD8+T-cells. Our findings demonstrate that metabolic reprogramming elicits anti-mIDH1 glioma immunity, leading to increased MS and immunological memory. Our preclinical data supports the testing of IDH-R132H inhibitors in combination with IR/TMZ and anti-PDL1 as targeted therapy for mIDH1/mATRX/mTP53 glioma patients.Brief SummaryInhibition of 2-Hydroxyglutrate in mutant-IDH1 glioma in the genetic context of ATRX and TP53 inactivation elicits metabolic-reprograming and anti-glioma immunity.
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- 2020
23. Inhibition of 2-hydroxyglutarate elicits metabolic reprogramming and mutant IDH1 glioma immunity in mice
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Lili Zhao, Felipe J Nunez, Jessica C. Gauss, Maria B. Garcia-Fabiani, Padma Kadiyala, Santiago Haase, Fernando M. Nunez, Henry D. Appelman, Ayman Taher, Yayuan Liu, Yilun Sun, Mahmoud S. Alghamri, Pedro R. Lowenstein, James J. Moon, Minzhi Yu, Maria G. Castro, Dan Li, Stephen Carney, Celina G. Kleer, Anna Schwendeman, and Marta Edwards
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0301 basic medicine ,X-linked Nuclear Protein ,IDH1 ,T cell ,CD8-Positive T-Lymphocytes ,Glutarates ,03 medical and health sciences ,Mice ,0302 clinical medicine ,Glioma ,Cell Line, Tumor ,Temozolomide ,Medicine ,Animals ,Humans ,neoplasms ,ATRX ,Tumor microenvironment ,business.industry ,General Medicine ,Chemoradiotherapy ,Acquired immune system ,medicine.disease ,Cellular Reprogramming ,Immune checkpoint ,Isocitrate Dehydrogenase ,030104 developmental biology ,medicine.anatomical_structure ,030220 oncology & carcinogenesis ,Gain of Function Mutation ,Cancer research ,Tumor Suppressor Protein p53 ,business ,Immunologic Memory ,medicine.drug ,Research Article - Abstract
Mutant isocitrate dehydrogenase 1 (IDH1-R132H; mIDH1) is a hallmark of adult gliomas. Lower grade mIDH1 gliomas are classified into 2 molecular subgroups: 1p/19q codeletion/TERT-promoter mutations or inactivating mutations in α-thalassemia/mental retardation syndrome X-linked (ATRX) and TP53. This work focuses on glioma subtypes harboring mIDH1, TP53, and ATRX inactivation. IDH1-R132H is a gain-of-function mutation that converts α-ketoglutarate into 2-hydroxyglutarate (D-2HG). The role of D-2HG within the tumor microenvironment of mIDH1/mATRX/mTP53 gliomas remains unexplored. Inhibition of D-2HG, when used as monotherapy or in combination with radiation and temozolomide (IR/TMZ), led to increased median survival (MS) of mIDH1 glioma–bearing mice. Also, D-2HG inhibition elicited anti–mIDH1 glioma immunological memory. In response to D-2HG inhibition, PD-L1 expression levels on mIDH1-glioma cells increased to similar levels as observed in WT-IDH gliomas. Thus, we combined D-2HG inhibition/IR/TMZ with anti–PDL1 immune checkpoint blockade and observed complete tumor regression in 60% of mIDH1 glioma–bearing mice. This combination strategy reduced T cell exhaustion and favored the generation of memory CD8(+) T cells. Our findings demonstrate that metabolic reprogramming elicits anti–mIDH1 glioma immunity, leading to increased MS and immunological memory. Our preclinical data support the testing of IDH-R132H inhibitors in combination with IR/TMZ and anti-PDL1 as targeted therapy for mIDH1/mATRX/mTP53 glioma patients.
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- 2020
24. Prospects of Biological and Synthetic Pharmacotherapies for Glioblastoma
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Marianela Candolfi, Mahmoud S. Alghamri, David B. Altshuler, Maria G. Castro, Felipe J Nunez, Padma Kadiyala, Antonela Sofía Asad, Stephen Carney, Anna Schwendeman, Joerg Lahann, Alejandro Javier Nicola Candia, Fernando M. Nunez, Pedro R. Lowenstein, James J. Moon, and Maria B. Garcia-Fabiani
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0301 basic medicine ,CIENCIAS MÉDICAS Y DE LA SALUD ,Genetic enhancement ,medicine.medical_treatment ,Immune checkpoint inhibitors ,Clinical Biochemistry ,GENE THERAPY ,Cancer Vaccines ,Immunotherapy, Adoptive ,Article ,03 medical and health sciences ,0302 clinical medicine ,Glioma ,IDH1 Mutation ,Drug Discovery ,Medicine ,Humans ,IMMUNE CHECKPOINT INHIBITORS ,IMMUNOTHERAPY ,Immune Checkpoint Inhibitors ,Pharmacology ,Oncolytic Virotherapy ,IDH1 MUTATION ,business.industry ,Brain Neoplasms ,Immunotherapy ,Genetic Therapy ,medicine.disease ,Isocitrate Dehydrogenase ,Otras Ciencias Médicas ,030104 developmental biology ,Nanomedicine ,030220 oncology & carcinogenesis ,Cancer research ,GLIOMA ,business ,Glioblastoma - Abstract
Introduction: The field of neuro-oncology has experienced significant advances in recent years. More is known now about the molecular and genetic characteristics of glioma than ever before. This knowledge leads to the understanding of glioma biology and pathogenesis, guiding the development of targeted therapeutics and clinical trials. The goal of this review is to describe the state of basic, translational, and clinical research as it pertains to biological and synthetic pharmacotherapy for gliomas. Areas covered: Challenges remain in designing accurate preclinical models and identifying patients that are likely to respond to a particular targeted therapy. Preclinical models for therapeutic assessment are critical to identify the most promising treatment approaches. Expert opinion: Despite promising new therapeutics, there have been no significant breakthroughs in glioma treatment and patient outcomes. Thus, there is an urgent need to better understand the mechanisms of treatment resistance and to design effective clinical trials. Fil: Altshuler, David B.. University of Michigan; Estados Unidos Fil: Kadiyala, Padma. University of Michigan; Estados Unidos Fil: Nuñez, Felipe J.. University of Michigan; Estados Unidos Fil: Nuñez, Fernando M.. University of Michigan; Estados Unidos Fil: Carney, Stephen. University of Michigan; Estados Unidos Fil: Alghamri, Mahmoud S.. University of Michigan; Estados Unidos Fil: Garcia Fabiani, Maria Belen. University of Michigan; Estados Unidos Fil: Asad, Antonela Sofía. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Biomédicas. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Biomédicas; Argentina Fil: Nicola Candia, Alejandro Javier. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Biomédicas. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Biomédicas; Argentina Fil: Candolfi, Marianela. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Biomédicas. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Biomédicas; Argentina Fil: Lahann, Joerg. University of Michigan; Estados Unidos Fil: Moon, James J.. University of Michigan; Estados Unidos Fil: Schwendeman, Anna. University of Michigan; Estados Unidos Fil: Lowenstein, Pedro R.. University of Michigan; Estados Unidos Fil: Castro, Maria G.. University of Michigan; Estados Unidos
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- 2020
25. Functional characterization of tumor antigen-specific T-cells isolated from the tumor microenvironment of sleeping beauty induced murine glioma models
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Mahmoud S. Alghamri, Felipe J Nunez, Maria G. Castro, Neha Kamran, Pedro R. Lowenstein, David Altshuler, and Stephen Carney
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medicine.medical_treatment ,Genetic enhancement ,T cell ,T-Lymphocytes ,Thymidine Kinase ,Article ,Mice ,Lymphocytes, Tumor-Infiltrating ,Antigen ,Antigens, Neoplasm ,Glioma ,medicine ,Tumor Microenvironment ,Animals ,Tumor microenvironment ,business.industry ,Brain Neoplasms ,Membrane Proteins ,Immunotherapy ,Genetic Therapy ,medicine.disease ,Cytotoxicity Tests, Immunologic ,Primary tumor ,Tumor antigen ,medicine.anatomical_structure ,Cancer research ,business ,Immunologic Memory - Abstract
Glioma is one of the most aggressive tumors. The median survival of the most aggressive form (Glioblastoma (GBM)) is approximately 14–20 months. The current standard of care includes tumor resection, chemotherapy and radiation, nevertheless, the incidence of recurrence remains high and there is a critical need for developing new therapeutic strategies. T-cell mediated immunotherapy that triggers an anti-tumor T cell-mediated memory response is a promising approach since it will not only attack the primary tumor but also prevent recurrence. Multiple immunotherapeutic strategies against glioma are currently being tested in clinical trials. We have developed an immune-mediated gene therapy (Thymidine kinase plus Fms-like tyrosine kinase 3 ligand: TK/Flt3L) which induces a robust anti-tumor T cell response leading to tumor regression, long-term survival and immunological memory in glioblastoma models. Efficacy of the anti-glioma T cell therapy is determined by anti-tumor specific effector T cells (Han et al., 2014). Therefore, assessing effector T cell activation status and function are critical readouts for assessing the effectiveness of the therapy. Here, we detail methodologies to evaluate tumor specific T-cell responses using a genetically engineered Sleeping Beauty transposase-mediated glioma model. We first describe the glioma model and the generation of neurospheres (NS) that express the surrogate antigen cOVA. Then, we describe functional assays to determine anti-tumor T-cell response.
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- 2020
26. Functional assay to assess T-cell inhibitory properties of myeloid derived suppressor cells (MDSCs) isolated from the tumor microenvironment of murine glioma models
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Maria G. Castro, Mahmoud S. Alghamri, Pedro R. Lowenstein, Padma Kadiyala, and Neha Kamran
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Functional assay ,T-Lymphocytes ,T cell ,medicine.medical_treatment ,030303 biophysics ,Cell Separation ,Inhibitory postsynaptic potential ,Article ,Mice ,03 medical and health sciences ,Immune system ,Glioma ,Immune Tolerance ,Tumor Microenvironment ,medicine ,Animals ,neoplasms ,Cells, Cultured ,Cell Proliferation ,0303 health sciences ,Tumor microenvironment ,Brain Neoplasms ,business.industry ,Myeloid-Derived Suppressor Cells ,Immunosuppression ,medicine.disease ,nervous system diseases ,Mice, Inbred C57BL ,Disease Models, Animal ,medicine.anatomical_structure ,Myeloid-derived Suppressor Cell ,Cancer research ,Female ,sense organs ,business - Abstract
Despite advances in uncovering the molecular mechanisms that mediate glioma progression and the implementation of novel therapeutic modalities, patients’ prognosis remains dismal. This is due to both systemic and local tumor induced immune suppression. We are particularly interested in the role played by infiltrating immunosuppressive myeloid derived suppressor cells (MDSCs) in the glioma tumor microenvironment (TME). This immunosuppressive TME also interferes with the effectiveness of immunotherapies against glioma. Development of multipronged treatment approaches is imperative when aiming to generate a robust anti-glioma immune response. Evaluating the inhibitory potential of MDSCs within the TME is an important aspect for developing effective treatments for glioma. Herein, we discuss methodology to assess the inhibitory effects of MDSCs isolated from the TME using a mouse glioma model.
- Published
- 2020
27. TMIC-35. IDH1 MUTATION IN GLIOMA REPROGRAMS EARLY MYELOID DIFFERENTIATION IN THE BONE MARROW (BM) TO PRODUCE NON-IMUNESUPPRESSIVE NEUTROPHILS
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Neha Kamran, Mahmoud S. Alghamri, Ruthvik Avvari, Maria G. Castro, Pedro R. Lowenstein, Li Zhang, and Padma Kadiyala
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Cancer Research ,Myeloid ,business.industry ,medicine.disease ,medicine.anatomical_structure ,Oncology ,Glioma ,IDH1 Mutation ,medicine ,Cancer research ,Tumor Microenvironment ,Neurology (clinical) ,Bone marrow ,business - Abstract
Gliomas are the most common primary brain tumors; patients exhibit a poor prognosis. Mutations in isocitrate dehydrogenase (mIDH) are present in most patients with lower grade glioma (LGG), and are correlated with better prognosis and survival. We postulated that mIDH1 induces epigenetic reprogramming leading to alteration in immune cells’ function. To examine the role of mIDH1 in the tumor immune microenvironment (TME), we generated LGG glioma models using the sleeping beauty system (Koschmann et al., 2016, Nunez et al., 2019). We show that mIDH1 gliomas exhibit increased levels of CD11b+ Gr1+ myeloid derived suppressor cells in the tumor, BM, circulation and spleen of mice. We found that mIDH1 modifies the cytokines’ repertoire in the glioma microenvironment altering the phenotype and function of the tumor infiltrating CD45+/CD11b+/Gr-1+ myeloid cells, rendering them non-immunosuppressive. Production of these cells results from activation of the granulocytic differentiation program in the BM. This novel mechanism is mediated by tumor-derived granulocyte-colony stimulating factor (G-CSF) which elicits expansion and differentiation of hematopoietic stem cells, skewing hematopoiesis towards the immature myeloid lineage. Moreover, mIDH1 glioma derived G-CSF causes mobilization of hematopoietic stem cells (HSCs) and myeloid progenitors (MPs) from BM to spleen. Blocking G-CSF in mIDH1 bearing mice significantly restored HSCs, and MPs frequencies in the spleen to levels encountered in wtIDH1 glioma. Interestingly, blocking G-CSF restored the inhibitory function of the granulocytic CD11b+ Gr-1+ in mIDH1, and shortened the median survival (MS) of mIDH1 bearing mice to the same MS encountered in wtIDH1 glioma. Our results provide insights into novel epigenetic alterations triggered by mIDH1 which regulate myeloid cells’ heterogeneity and immunosuppression; a feature that can be harnessed to develop novel immunotherapeutic strategies.
- Published
- 2019
28. TMOD-02. CHARACTERIZATION OF THE TUMOR IMMUNE MICROENVIRONMENT IN A PEDIATRIC HIGH GRADE GLIOMA MOUSE MODEL HARBORING THE H3.3-G34R MUTATION
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Maria Garcia Fabiani, Santiago Haase, Felipe J Nunez, Andrea Comba, Padma Kadiyala, Maria G. Castro, Mahmoud S. Alghamri, Pedro R. Lowenstein, and Matthew J. Whalen
- Subjects
Cancer Research ,Mutation ,Tumor microenvironment ,biology ,medicine.disease_cause ,medicine.disease ,Phenotype ,Pediatric Brain Tumor Models ,Histone ,Immune system ,Oncology ,Glioma ,biology.protein ,Cancer research ,medicine ,Myeloid-derived Suppressor Cell ,Neurology (clinical) ,Signal transduction - Abstract
Pediatric high grade gliomas (pHGGs) have a median survival (MS) of 9–15 months, are the most common malignant brain tumors in children and no significant improvement in the MS of these patients has been registered in decades. Thus, a representative in vivo model to study this tumor is critical. Recurrent mutations in genes encoding histones H3.3 and H3.1 have been described, which are distinctive of pHGGs. We aimed to establish a mouse model for pHGG harboring the mutation H3.3 G34R, which co-occurs with inactivating mutations in ATRX and TP53. To induce HGG, we used the Sleeping Beauty transposase system in which tumors are induced intrinsically in the mouse brain after injection of plasmids harboring the desired genetic alterations. The WT-H3.3 group pHGGs are generated after the injection of 4 plasmids, i.e., expressing mutated NRAS-G12V (activating mutation) + short hairpins against Tp53 and Atrx + the mutated histone H3.3-G34R (H3.3-G34R group). As controls, we injected plasmids overexpressing mutated NRAS-G12V + short hairpins against Tp53 and Atrx (WT-H3.3 group). H3.3-G34R group have longer MS when compared to the WT-H3.3 group (p
- Published
- 2019
29. IDH1-R132H acts as a tumor suppressor in glioma via epigenetic upregulation of the DNA damage response
- Author
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Cameron Herting, Mats Ljungman, Maria B. Garcia-Fabiani, Mahmoud S. Alghamri, Vera Gorbunova, Tingting Qin, Masha G. Savelieff, Marta Edwards, Padma Kadiyala, Dolores Hambardzumyan, Anda Alexandra Calinescu, Rebecca Tagett, Neha Kamran, Carl Koschmann, Maria E. Figueroa, Pedro R. Lowenstein, Alan K. Meeker, Santiago Haase, James Ross, Lindsey E Jones, Felipe J Nunez, Jacqueline A. Brosnan-Cashman, Daniel M. Kremer, Sriram Venneti, Lili Zhao, Stephen Carney, Li Zhang, Rohin Patel, Flor M. Mendez, Costas A. Lyssiotis, Shawn L. Hervey-Jumper, Maureen A. Sartor, Maria G. Castro, Marissa Z Guo, and Meghna Saxena
- Subjects
Genome instability ,IDH1 ,DNA Repair ,DNA repair ,DNA damage ,Ataxia Telangiectasia Mutated Proteins ,Biology ,medicine.disease_cause ,Radiation Tolerance ,Article ,Epigenesis, Genetic ,Histones ,03 medical and health sciences ,Mice ,0302 clinical medicine ,Radioresistance ,Glioma ,medicine ,Animals ,Humans ,CHEK1 ,Epigenetics ,ATRX ,030304 developmental biology ,0303 health sciences ,Mutation ,Genome ,Brain Neoplasms ,Tumor Suppressor Proteins ,Cell Differentiation ,General Medicine ,DNA Methylation ,medicine.disease ,Survival Analysis ,Isocitrate Dehydrogenase ,3. Good health ,Up-Regulation ,Disease Models, Animal ,Oligodendroglia ,Gene Ontology ,030220 oncology & carcinogenesis ,Cancer research ,DNA Damage ,Signal Transduction - Abstract
Patients with glioma whose tumors carry a mutation in isocitrate dehydrogenase 1 (IDH1 R132H ) are younger at diagnosis and live longer. IDH1 mutations co-occur with other molecular lesions, such as 1p/19q codeletion, inactivating mutations in the tumor suppressor protein 53 (TP53 ) gene, and loss-of-function mutations in alpha thalassemia/mental retardation syndrome X-linked gene ( ATRX ). All adult low-grade gliomas (LGGs) harboring ATRX loss also express the IDH1 R132H mutation. The current molecular classification of LGGs is based, partly, on the distribution of these mutations. We developed a genetically engineered mouse model harboring IDH1 R132H , TP53 and ATRX inactivating mutations, and activated NRAS G12V. Previously, we established that ATRX deficiency, in the context of wild-type IDH1, induces genomic instability, impairs nonhomologous end-joining DNA repair, and increases sensitivity to DNA-damaging therapies. In this study, using our mouse model and primary patient-derived glioma cultures with IDH1 mutations, we investigated the function of IDH1 R132H in the context of TP53 and ATRX loss. We discovered that IDH1 R132H expression in the genetic context of ATRX and TP53 gene inactivation (i) increases median survival in the absence of treatment, (ii) enhances DNA damage response (DDR) via epigenetic up-regulation of the ataxia-telangiectasia–mutated (ATM) signaling pathway, and (iii) elicits tumor radioresistance. Accordingly, pharmacological inhibition of ATM or checkpoint kinases 1 and 2, essential kinases in the DDR, restored the tumors’ radiosensitivity. Translation of these findings to patients with IDH1 132H glioma harboring TP53 and ATRX loss could improve the therapeutic efficacy of radiotherapy and, consequently, patient survival.
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- 2019
30. IMMU-63. IDH1 MUTATION REGULATE MYELOID CELLS PLASTICITY MEDIATING ANTI-GLIOMA IMMUNOTHERAPY
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Felipe J Nunez, Mahmoud S. Alghamri, Maria G. Castro, Neha Kamran, Ruthvik Avvari, Padma Kadiyala, Pedro R. Lowenstein, and Li Zhang
- Subjects
Cancer Research ,Abstracts ,Oncology ,medicine.medical_treatment ,IDH1 Mutation ,Glioma ,Myeloid cells ,medicine ,Cancer research ,Neurology (clinical) ,Immunotherapy ,Biology ,medicine.disease - Abstract
Molecular characterization studies have illustrated that mutation in isocitrate dehydrogenase (mIDH1) enzyme, which is present in most patients with low grade glioma (LGG) and secondary glioma is correlated with better prognosis and survival [1]. We hypothesize that mIDH1 impacts tumor immunity by altering the phenotype and function of tumor infiltrating immune cells. To examine the role of mIDH1 on the immune tumor microenvironment (TME), we generated LGG glioma models using sleeping beauty system [2]. Mice bearing mIDH1 tumors exhibited longer median survival (MS) compared to the tumors harboring wtIDH1 (MS=163 vs. MS=70-day post-injection). Transcriptome analyses showed a positive enrichment in immune-stimulatory related gene families in mIDH1 tumors vs. wtIDH1 tumors; consistent with Human RNA-seq analysis from TCGA analysis. Using co-culture experiments followed by the in vivo characterization of immune cells within the TME, we showed that mIDH1 have higher expansion of CD11b+ Gr-1+ myeloid cells compared to wtIDH1 tumors (%MDSC/CD45+: 67.0% vs. 45.06%; P
- Published
- 2018
31. CSIG-07. COMPARATIVE RNA-SEQ ANALYSIS OF GLIOMAS OF DIFFERENT MALIGNANCY IDENTIFIES FYN AS A NOVEL REGULATOR OF GBM AGGRESSIVENESS
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Maria G. Castro, Mahmoud S. Alghamri, Andrea Comba, Pedro R. Lowenstein, Padma Kadiyala, Felipe J Nunez, Patrick Dunn, Priti Patel, and Anna E Argento
- Subjects
Cancer Research ,Abstracts ,FYN ,Oncology ,Cancer research ,medicine ,Regulator ,RNA-Seq ,Neurology (clinical) ,Biology ,Malignancy ,medicine.disease - Abstract
Glioblastomas (GBM) are the most frequent and aggressive primary tumors of the brain. Fyn, a Src family kinase member, is overexpressed in human GBM. Its function, however, remains poorly understood. We analyzed the differential gene expression (DE) of highly malignant tumor (NPA: N-Ras/shp53/shATRx) compared to a less malignant one (NPAI: N-Ras/shp53/shATRx/IDH1R132H). Bioinformatics and network analysis identified Fyn as a highly connected node. This suggests that Fyn could be a regulator of GBM growth and progression. We therefore investigated the role of Fyn on glioma function in vitro and in vivo. Fyn expression levels in both human and mouse GBM cells correlated with tumor aggressiveness. Fyn knockdown in NP and NPA glioma cells decreased cell proliferation and migration. To test the activity of Fyn on tumor growth in vivo, we developed a Fyn-deficient glioma genetic model using the Sleeping Beauty transposase system. We induced Fyn knockdown in glioma tumors with different genetic drivers: NPF: N-Ras/shp53+shFyn, NPAF: N-Ras/shp53/shATRx+shFYN and NPDF: N-Ras/shp53/PDGFβ+shFYN. Fyn knockdown increased survival in all three genetically different tumors. The absence of Fyn reduced malignant neuropathological features such as pseudopalisades, ischemic necrosis, and microvascular proliferation. At the molecular level, RNA-Seq and DE analysis comparing NPF tumors with their controls, NP tumors (N-Ras/shp53) identified 573 differentially expressed genes. Bioinformatics analysis indicated altered activity in the following Gene Ontologies: “regulation of cell adhesion”, “inflammatory response”, and “positive regulation of cell motility”. In addition, signaling pathways significantly altered in their activity included “cell adhesion molecules (CAMs)”, “focal adhesion” and “ECM receptor interaction”. Our results indicate that Fyn would exert its effects by regulating cell motility and interactions with the ECM. We suggest that inhibiting Fyn activity, a novel regulator of glioma malignancy, could become a relevant treatment for GBM.
- Published
- 2018
32. TAMI-52. G-CSF SECRETED BY EPIGENETICALLY REPROGRAMMED MUTANT IDH1 GLIOMA STEM CELLS, REVERSES THE MYELOID CELLS’-MEDIATED IMMUNOSUPPRESSIVE TUMOR MICROENVIRONMENT
- Author
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Patil Pg, Karen Eddy, Jason Heth, Gao C, Gabriel Núñez, Welch J, Shawn L. Hervey-Jumper, Stephen Carney, Rohit Thalla, Mahmoud S. Alghamri, Li Zhang, Daniel A. Orringer, Neha Kamran, Ruthvik Avvari, Felipe J Nunez, Maria B. Garcia-Fabiani, Liu J, Ulintz Pj, Maria Ventosa, Merajver S, Pedro R. Lowenstein, Syed M Faisal, Santiago Haase, Dolores Hambardzumyan, Ayman Taher, Wajd N. Al-Holou, and Maria G. Castro
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Cancer Research ,Tumor microenvironment ,IDH1 ,Mutant ,Tumor Microenvironment/Angiogenesis/Metabolism/Invasion ,Biology ,medicine.disease ,Oncology ,Glioma ,Myeloid cells ,medicine ,Cancer research ,Neurology (clinical) ,Stem cell - Abstract
Mutation in isocitrate dehydrogenase (mIDH) is the main genetic lesion that defines clinical glioma subtypes and prognosis. This gain of function mutation is associated with the production of the oncometabolite, R-2-hydroxyglutarate, that inhibits α-ketoglutarate dependent enzymes such as TET2 and the Jumonji-C domain containing demethylases. The resultant epigenetic modifications elicit profound effects on the tumor biology and on the glioma-infiltrating immune cells. Here, we report that in genetically engineered mouse glioma models(1), IDH1 mutation caused an expansion of tumor infiltration granulocytes. Upon phenotypic and functional characterization, we uncovered that granulocytes in mIDH1 glioma express low level of immunosuppressive molecules and did not inhibit T-cell function. Single-cell sequencing revealed that these granulocytes are heterogeneous and composed of three distinct populations; neutrophils, pre-neutrophils, and a small fraction of immunosuppressive PMN-MDSCs. Moreover, primary human gliomas showed a higher cellular fraction exhibiting the PMN-MDSCs gene signature in wtIDH1 tumors than the mIDH1 tumors. The mechanism by which mIDH1 mediates non-immune suppressive granulocytes expansion involves epigenetic reprogramming which leads to enhanced expression of granulocyte colony-stimulating factor (G-CSF) in stem-like cells. High G-CSF gene expression is correlated with favorable patient outcome solely in LGG-astrocytoma with mIDH1. Thus, G-CSF represents a potential therapeutic that can be harnessed to improve immunotherapeutic responses in wild type IDH1 glioma patients.
- Published
- 2020
33. PDTM-20. THE HISTONE MUTATION H3.3-G34R ENCOUNTERED IN PEDIATRIC HIGH GRADE GLIOMA MODIFIES THE TUMOR IMMUNE MICROENVIRONMENT RENDERING IT MORE PERMISSIVE FOR IMMUNE MEDIATED THERAPIES
- Author
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Felipe J Nunez, Maria B. Garcia-Fabiani, Santiago Haase, Maria G. Castro, Mahmoud S. Alghamri, Pedro R. Lowenstein, Matthew J. Whalen, Padma Kadiyala, and Andrea Comba
- Subjects
Cancer Research ,Mutation ,Tumor microenvironment ,biology ,Pediatric Tumors ,business.industry ,medicine.disease_cause ,medicine.disease ,Phenotype ,Immune system ,Histone ,Oncology ,Glioma ,medicine ,Myeloid-derived Suppressor Cell ,biology.protein ,Cancer research ,Neurology (clinical) ,Permissive ,business - Abstract
Pediatric high grade gliomas (pHGGs) have a median survival (MS) of 9–15 months and are the most common malignant brain tumors in children. No significant improvement in the MS of these patients has been registered in decades. Thus, a representative in vivo model to study these tumors is critical. Recurrent mutations in genes encoding histones H3.3 and H3.1 have been described, which are distinctive of pHGGs. To stablish a mouse model for pHGG harboring the mutation H3.3-G34R, which co-occurs with inactivating mutations in ATRX and TP53, we used the Sleeping Beauty transposase system (H3.3-G34R group). The MS of mice harboring H3.3-G34R mutation was significantly longer than the MS of the WT-H3.3 control group (p< 0.0001). We performed RNA-Sequencing of these tumors which yielded 233 differentially expressed genes between these two groups (p< 0.05). Gene set enrichment analysis of the upregulated genes in H3.3-G34R group showed significant GOs related to immune response activation and response to IFNγ. Thus, we next studied the tumor microenvironment (TME) to determine the distinctive immune cell populations, at the phenotypic and functional level. We observed that the H3.3-G34R TME exhibited less frequency of Gr-1+/CD11b+ cells (myeloid-derived suppressor cells: MDSC). MDSC are immature myeloid cells that impair T cell functions and the adaptive immune response. Moreover, the H3.3-G34R TME had increased numbers of total macrophages (p< 0.05), a higher proportion of M1 anti-tumor macrophages, and higher levels of CD8+ T cells (p< 0.01). Also, the H3.3-G34R renders glioma cells more sensitive to IFNγ regulation as it induced a higher pSTAT1/STAT1 ratio in H3.3-G34R cells. These results shed light on the interaction between the immune system and the H3.3-G34R glioma cells and how this could be harnessed to develop immune mediated therapies specific for pHGG harboring the H3.3-G34R mutation.
- Published
- 2019
34. IMMU-58. IDH1 MUTATION REGULATES MYELOID CELLS MEDIATED IMMUNOSUPPRESSION IN GLIOMA
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Maria G. Castro, Mahmoud S. Alghamri, Pedro R. Lowenstein, Neha Kamran, and Felipe J Nunez
- Subjects
Cancer Research ,business.industry ,medicine.medical_treatment ,Immunosuppression ,medicine.disease ,Abstracts ,Text mining ,Oncology ,IDH1 Mutation ,Glioma ,Myeloid cells ,Immunology ,Cancer research ,medicine ,Neurology (clinical) ,business - Abstract
Molecular characterization studies have led to uncover the genetic signatures and methylation status of gliomas and correlate these with clinical prognosis. These studies have illustrated that mutation in isocitrate dehydrogenase (mIDH1), and far less common mIDH2, enzymes present in most patients with low grade and secondary glioma. Moreover, glioma patients with mIDH1 show better prognosis and survival. We hypothesize that mIDH1 impacts tumor immunity by altering the phenotype and function of tumor infiltrating immune cells. To examine the role of mIDH1, we generated glioma models containing the following genetic lesions; NRASG12V, shp53, and shATRx with or without mIDH1. The mouse models investigated are: mIDH1 tumors (NRASG12V+ shp53+ shATRX+ mIDH1) or wtIDH1 tumors (NRASG12V+ shp53+ shATRX+ wtIDH1). Mice bearing mIDH1 tumors exhibited longer median survival (MS) compared to the tumors harboring wtIDH1 (MS=163 vs. MS=70 days post-injection). Transcriptome analyses showed a positive enrichment in immune-stimulatory related gene families in mIDH1 tumors vs. wtIDH1 tumors. Flow cytometric characterization of immune cells showed higher expansion of CD11b+Gr-1+ myeloid cells in the tumor microenvironment (TME) and spleen of mIDH1 compared to wtIDH1 tumors (%MDSC/CD45+: 47.0% vs. 18.06%; P
- Published
- 2017
35. Novel role of aminopeptidase-A in angiotensin-(1–7) metabolism post myocardial infarction
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Khalid M. Elased, Mariana Morris, Nadja Grobe, J. Gary Meszaros, and Mahmoud S. Alghamri
- Subjects
Male ,medicine.medical_specialty ,Cardiovascular Neurohormonal Regulation ,Physiology ,education ,Angiotensin III ,Myocardial Infarction ,Peptidyl-Dipeptidase A ,Glutamyl Aminopeptidase ,Substrate Specificity ,Mice ,Tandem Mass Spectrometry ,Physiology (medical) ,Internal medicine ,mental disorders ,Renin–angiotensin system ,Animals ,Medicine ,Myocardial infarction ,Enzyme Inhibitors ,Ventricular remodeling ,chemistry.chemical_classification ,Ventricular Remodeling ,business.industry ,Angiotensin II ,Myocardium ,Metabolism ,medicine.disease ,Peptide Fragments ,Mice, Inbred C57BL ,Disease Models, Animal ,Kinetics ,Endocrinology ,Enzyme ,chemistry ,Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization ,Glutamyl aminopeptidase ,cardiovascular system ,Angiotensin-Converting Enzyme 2 ,Angiotensin I ,Cardiology and Cardiovascular Medicine ,business ,psychological phenomena and processes ,hormones, hormone substitutes, and hormone antagonists - Abstract
Aminopeptidase-A (APA) is a less well-studied enzyme of the renin-angiotensin system. We propose that it is involved in cardiac angiotensin (ANG) metabolism and its pathologies. ANG-(1–7) can ameliorate remodeling after myocardial injury. The aims of this study are to 1) develop mass spectrometric (MS) approaches for the assessment of ANG processing by APA within the myocardium; and 2) investigate the role of APA in cardiac ANG-(1–7) metabolism after myocardial infarction (MI) using sensitive MS techniques. MI was induced in C57Bl/6 male mice by ligating the left anterior descending (LAD) artery. Frozen mouse heart sections (in situ assay) or myocardial homogenates (in vitro assay) were incubated with the endogenous APA substrate, ANG II. Results showed concentration- and time-dependent cardiac formation of ANG III from ANG II, which was inhibited by the specific APA inhibitor, 4-amino-4-phosphonobutyric acid. Myocardial APA activity was significantly increased 24 h after LAD ligation (0.82 ± 0.02 vs. 0.32 ± 0.02 ρmol·min−1·μg−1, MI vs. sham, P < 0.01). Both MS enzyme assays identified the presence of a new peptide, ANG-(2–7), m/z 784, which accumulated in the MI (146.45 ± 6.4 vs. 72.96 ± 7.0%, MI vs. sham, P < 0.05). Use of recombinant APA enzyme revealed that APA is responsible for ANG-(2–7) formation from ANG-(1–7). APA exhibited similar substrate affinity for ANG-(1–7) compared with ANG II { Km(ANG II) = 14.67 ± 1.6 vs. Km[ANG-(1–7)] = 6.07 ± 1.12 μmol/l, P < 0.05}. Results demonstrate a novel role of APA in ANG-(1–7) metabolism and suggest that the upregulation of APA, which occurs after MI, may deprive the heart of cardioprotective ANG-(1–7). Thus APA may serve as a potentially novel therapeutic target for management of tissue remodeling after MI.
- Published
- 2014
36. Enhanced Angiotensin II-Induced Cardiac and Aortic Remodeling in ACE2 Knockout Mice
- Author
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Nathan M. Weir, Mahmoud S. Alghamri, Susan B. Gurley, Mark P. Anstadt, Mariana Morris, and Khalid M. Elased
- Subjects
Male ,Cardiac function curve ,Mean arterial pressure ,medicine.medical_specialty ,Blood Pressure ,Peptidyl-Dipeptidase A ,Mice ,Heart Rate ,medicine.artery ,Internal medicine ,medicine ,Animals ,Pharmacology (medical) ,Ventricular remodeling ,Aorta ,Infusion Pumps ,Mice, Knockout ,Pharmacology ,Ejection fraction ,Ventricular Remodeling ,business.industry ,Angiotensin II ,Hypertrophic cardiomyopathy ,medicine.disease ,Mice, Inbred C57BL ,Endocrinology ,Angiotensin-converting enzyme 2 ,cardiovascular system ,Angiotensin-Converting Enzyme 2 ,Cardiology and Cardiovascular Medicine ,business ,hormones, hormone substitutes, and hormone antagonists - Abstract
Angiotensin-converting enzyme 2 (ACE2) is present in the heart and thought to exert protective functions. We conducted studies in ACE2 deficient mice to determine whether enzyme loss would exacerbate the cardiac and vascular pathological responses to chronic subcutaneous (sc) angiotensin II (Ang II) infusion. Eight-week-old male ACE2 knockout (KO) and wild type (WT) mice were infused with Ang II (1000 ng/kg per min, 4 weeks) using mini-osmotic pumps. Blood pressure (radiotelemetry), cardiac function (echocardiography, echo), cardiac/aortic structure (histology, collagen, and oxidative stress), and vascular inflammation were examined. Before Ang II infusion, ACE2 KO mice showed unaltered cardiac function and blood pressure. After 4 weeks of Ang II infusion, the mean arterial pressure (MAP) increased from 96 ± 2 to 136 ± 17 mm Hg (∼40%) in WT and from 104 ± 5 to 141 ± 13 mm Hg (∼ 35%) in ACE2 KO. While there were no differences in MAP between groups, the ACE2 KO responded differently to the hypertensive stimulus. Echo analysis revealed severe myocardial dysfunction in Ang II-infused ACE2 KO (Ang ACE2 KO). Ejection fraction was lower (39% versus 50%) as was fractional shortening (27% versus 38%) in ACE2 KO versus WT, respectively. Cardiac dysfunction was associated with hypertrophic cardiomyopathy shown by increased left-ventricular wall thickness, average cardiomyocyte cross-sectional area, and heart weight/body weight ratio. Collagen staining in the myocardium and aorta revealed increased collagen in Ang ACE2 KO, suggestive of remodeling. Results also showed enhanced oxidative stress in the myocardium and aorta of Ang ACE2 KO. There was a 3-fold elevation in macrophage inflammatory protein 1α (MIP 1α) in the aorta of ACE2 KO. Studies in the ACE2 KO model reveal the importance of ACE2 in the maladaptive cardiac and aortic responses to Ang II stimulation, seen as enhanced remodeling using physiological, structural, and biochemical markers. Results document a cardio- and vascular-protective role of ACE2 under pathological conditions.
- Published
- 2012
37. Melanoma induced immunosuppression is mediated by hematopoietic dysregulation
- Author
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Youping Li, Mahmoud S. Alghamri, Maria G. Castro, Neha Kamran, Pedro R. Lowenstein, Marta Edwards, María Teresa Mata Sierra, Henry D. Appelman, and Padma Kadiyala
- Subjects
lcsh:Immunologic diseases. Allergy ,0301 basic medicine ,Myeloid ,Immunology ,Biology ,myeloid derived suppressor cells ,lcsh:RC254-282 ,03 medical and health sciences ,immunosuppressive ,0302 clinical medicine ,Immune system ,medicine ,tumor microenvironment ,Immunology and Allergy ,Progenitor cell ,Tumor microenvironment ,tumor associated macrophages ,lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,Haematopoiesis ,030104 developmental biology ,medicine.anatomical_structure ,Oncology ,030220 oncology & carcinogenesis ,Cancer research ,Myeloid-derived Suppressor Cell ,Bone marrow ,Stem cell ,lcsh:RC581-607 - Abstract
Tumors are associated with expansion of immunosuppressive cells such as tumor associated macrophages (TAMs), regulatory T cells (Tregs) and myeloid derived suppressor cells (MDSCs). These cells promote tumor growth, angiogenesis, metastasis and immune escape. Cancer patients frequently present symptoms such as anemia, leukocytosis and/or cytopenia; associated with poor prognosis. To uncover tumor-mediated hematopoietic abnormalities and identify novel targets that can be harnessed to improve tumor-specific immune responses, we investigated the hematopoietic stem and progenitor cell compartment in melanoma bearing mice. We show that melanoma growth results in expansion of myeloid lineages such as MDSCs, macrophages and DCs along with a reduction in mature RBCs and platelets. Mature B lymphocytes in the blood and BM of melanoma mice were also reduced. Mice bearing melanoma showed extramedullary hematopoiesis in the spleen. Increased expansion of myeloid lineages occurred directly at the level of stem and progenitor cells. The reduction in mature B lymphocytes resulted from a block at the Pro-B cell stage in the bone marrow. Addition of recombinant IL-3 to bone marrow cells resulted in the expansion of committed myeloid progenitors including common myeloid precursors, granulocyte-monocyte precursors and megakaryocyte-erythrocyte precursors. In vivo, IL-3 receptor stimulation in melanoma bearing mice using an IL-3 antibody also resulted in a robust expansion of committed myeloid progenitors and hematopoietic stem cells. Collectively our findings demonstrate that tumor growth plays a pivotal role in reprogramming the host immune system by impacting hematopoiesis directly at the level of stem cell compartment.
- Published
- 2017
38. Adenovirus Entry From the Apical Surface of Polarized Epithelia Is Facilitated by the Host Innate Immune Response
- Author
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Poornima L.N. Kotha, Julian Gomez-Cambronero, Trisha L. Brockman, Abimbola O. Kolawole, Ran Yan, Katherine J. D. A. Excoffon, Priyanka Sharma, and Mahmoud S. Alghamri
- Subjects
lcsh:Immunologic diseases. Allergy ,Neutrophils ,Adenoviridae Infections ,Immunology ,Biology ,medicine.disease_cause ,Microbiology ,Epithelium ,Proinflammatory cytokine ,Adenoviridae ,03 medical and health sciences ,Mice ,Immunity ,Viral entry ,Virology ,Genetics ,medicine ,Animals ,Humans ,Receptor ,Molecular Biology ,Protein kinase B ,lcsh:QH301-705.5 ,Cells, Cultured ,030304 developmental biology ,0303 health sciences ,Innate immune system ,030302 biochemistry & molecular biology ,Epithelial Cells ,Immunity, Innate ,3. Good health ,Cell biology ,medicine.anatomical_structure ,lcsh:Biology (General) ,Receptors, Virus ,Parasitology ,lcsh:RC581-607 ,Research Article - Abstract
Prevention of viral-induced respiratory disease begins with an understanding of the factors that increase or decrease susceptibility to viral infection. The primary receptor for most adenoviruses is the coxsackievirus and adenovirus receptor (CAR), a cell-cell adhesion protein normally localized at the basolateral surface of polarized epithelia and involved in neutrophil transepithelial migration. Recently, an alternate isoform of CAR, CAREx8, has been identified at the apical surface of polarized airway epithelia and is implicated in viral infection from the apical surface. We hypothesized that the endogenous role of CAREx8 may be to facilitate host innate immunity. We show that IL-8, a proinflammatory cytokine and a neutrophil chemoattractant, stimulates the protein expression and apical localization of CAREx8 via activation of AKT/S6K and inhibition of GSK3β. Apical CAREx8 tethers infiltrating neutrophils at the apical surface of a polarized epithelium. Moreover, neutrophils present on the apical-epithelial surface enhance adenovirus entry into the epithelium. These findings suggest that adenovirus evolved to co-opt an innate immune response pathway that stimulates the expression of its primary receptor, apical CAREx8, to allow the initial infection the intact epithelium. In addition, CAREx8 is a new target for the development of novel therapeutics for both respiratory inflammatory disease and adenoviral infection., Author Summary Respiratory viral infection is one of the leading causes of morbidity and mortality worldwide. Interventions that are able to limit viral infection will enhance human health and productivity. However, the mechanisms that control our susceptibility to viral infection and the factors that allow viral pathogens to breach the exterior epithelial barrier to initiate infection are not well understood. Here we find that adenovirus, a common cold virus and a potential gene therapy vector, uses a cellular receptor that is induced by the host innate immune response. Moreover, neutrophils, cells that are meant to protect the host in the early phase of an innate immune response, instead facilitate adenovirus infection. It has been known for over 15 years that adenovirus itself can induce an innate immune response and specifically induce host cell secretion of IL-8, a critical chemokine that attracts neutrophils to sites of infection. However, until now, it has been unclear how IL-8 induction might benefit the virus. Our data indicate that adenovirus evolved to use our innate defense system to enhance entry into the epithelium and identifies the apical adenovirus receptor as a new target that may modulate inflammatory disease.
- Published
- 2015
39. Abstract 205: Role of AT1a Receptor in Cardiac Function and Acid Base Homeostasis during Exercise Endurance
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Ahmad M Alhajoj, Mahmoud S. Alghamri, Roberta L. Pohlman, Debora Nakamoto, Nadja Grobe, and Mariana Morris
- Subjects
Cardiac function curve ,medicine.medical_specialty ,Ejection fraction ,Angiotensin II receptor type 1 ,business.industry ,Acid–base homeostasis ,medicine.disease ,Endocrinology ,Internal medicine ,Renin–angiotensin system ,Internal Medicine ,medicine ,Aerobic exercise ,business ,Receptor ,Acid–base imbalance - Abstract
Angiotensin Type 1 (AT1) receptors are involved in cardiovascular pathology. Lozartan, the AT1 receptor blocker, in combination with exercise has been shown to be effective in improving cardiac performance. The goal of the study was to investigate the role of AT1a receptors on cardiac function, and exercise tolerance in response to aerobic exercise using AT1a receptor knockout (AT1aKO) mice. An exercise wheel system was used for the exercise paradigm. Male (C57BL/6) wild type (WT) and AT1aKO mice were randomly assigned to four groups: WT control (n=6), WT exercise (WTEX, n=8), AT1a KO (KO) control (n=5), and AT1a KO exercise (KOEX, n=8). Mice were forced to run at a velocity of 8 m/min for 1 hour, 3d/wk, for 7 wks. Echocardiography was conducted at baseline and 7 wks. Lactate was measured during several exercise sessions. Electrolytes and cardiac histology were assessed post-sacrifice. Results showed a significant increase in ejection fraction (EF%) in KOEX (72.5±1.5%) vs. WTEX and KO control (63.4±1.2% and 63.2±2.2%, respectively). Mitral valve assessment revealed a marked decrease in E-wave velocity in WTEX compared to WT control at baseline (74±1.9 vs.90±3.5 cm/s, p p p 3 - ] in KOEX vs. WTEX (21.7±0.6 vs. 13.7±1.8 mmol/l). Cl - was lower in KOEX compared to WTEX (102.5±2.5 vs. 113.5±2.7mmol/l, p
- Published
- 2013
40. 319. Improving the Odds of Adenovirus-Mediated Gene Therapy By Upregulation of the Coxsackievirus and Adenovirus Receptor
- Author
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Katherine J. D. A. Excoffon, Priyanka Sharma, Mahmoud S. Alghamri, Abimbola O. Kolawole, Poornima L.N. Kotha, Brockman L. Brockman, Ran Yan, and Julian Gomez-Cambronero
- Subjects
Pharmacology ,P70-S6 Kinase 1 ,Biology ,Coxsackievirus ,medicine.disease ,biology.organism_classification ,Epithelium ,Proinflammatory cytokine ,Cell biology ,medicine.anatomical_structure ,Downregulation and upregulation ,Drug Discovery ,Immunology ,Genetics ,medicine ,Molecular Medicine ,Adenovirus infection ,Receptor ,Molecular Biology ,Protein kinase B - Abstract
Adenovirus-mediated gene therapy has been limited by the fact that the primary receptor for most adenovirus serotypes, the Coxsackievirus and adenovirus receptor (CAR), is inaccessible or not expressed on many cell types of interest. Few mechanisms have been discovered that regulate CAR expression and tissue specific localization. In the airway, CAR is mostly considered a cell-cell adhesion protein localized at the basolateral surface of polarized epithelia. Recently, an alternate isoform of CAR, CAREx8, has been identified at the apical surface of polarized airway epithelia and is implicated in viral infection from the apical surface. We hypothesized that upregulation of cellular mechanisms that facilitate endogenous CAREx8 protein expression at the apical surface would enhance adenovirus gene transfer. Using polarized model epithelial cell lines and primary human airway epithelia, we found that IL-8, a proinflammatory cytokine and a neutrophil chemoattractant, stimulates the protein expression and apical localization of CAREx8 via activation of AKT/S6K and inhibition of GSK3β. IL-8- mediated upregulation of CAREx8 increased AdV5-β-Gal entry and transduction by approximately 5-fold. Moreover, we found that infiltrating neutrophils bind CAREx8 at the apical surface of a polarized epithelium and, surprisingly, neutrophils enhance AdV5-β-Gal entry into the epithelium by 2-3 fold. The effect of IL-8 and neutrophils on AdV infection could be blocked by fiber-knob from AdV5 but not AdV3, a non-CAR binding serotype, indicating the importance of CAR. These findings suggest that acute inflammation may enhance adenovirus infection. Moreover, therapeutics that stimulate the AKT/S6K pathway or inhibit GSK3β may be able to augment adenovirus-mediated gene therapy.
- Published
- 2015
41. Inactivation of AT1a Receptor Attenuates Lactate Accumulation and Enhances Cardiac Performance during Exercise Endurance
- Author
-
Mariana Morris, Mahmoud S. Alghamri, Debora Nakamoto, Ahmad M Alhajoj, and Roberta L. Pohlman
- Subjects
medicine.medical_specialty ,Endocrinology ,Chemistry ,Internal medicine ,At1a receptor ,medicine ,Physical Therapy, Sports Therapy and Rehabilitation ,Orthopedics and Sports Medicine - Published
- 2014
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