Rohit Thalla

Loyola University Chicago

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Mahmoud S. Alghamri

University of Michigan–Ann Arbor

Pedro R. Löwenstein

University of Michigan–Ann Arbor

María G. Castro

University of Michigan–Ann Arbor

Ayman Taher

University of Michigan–Ann Arbor

Ruthvik Avvari

University of Michigan–Ann Arbor

Syed Mohd Faisal

University of Michigan–Ann Arbor

Stephen V. Carney

University of Michigan–Ann Arbor

Brandon L. McClellan

University of Michigan–Ann Arbor

Ali Dabaja

Henry Ford Health System

Michael R. Olin

University of Minnesota

Cooperative Institutions

University of Michigan–Ann Arbor

Ann Arbor Center for Independent Living

Michigan Medicine

U-M Rogel Cancer Center

BioSurfaces (United States)

Regional West Medical Center

Loyola University Medical Center

Loyola University Chicago

Michigan United

Consejo Nacional de Investigaciones Científicas y Técnicas

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Targeting Neuroinflammation in Brain Cancer: Uncovering Mechanisms, Pharmacological Targets, and Neuropharmaceutical Developments

Frontiers in Pharmacology (2021)

Mahmoud S. Alghamri Brandon L. McClellan Carson S. Hartlage Santiago Haase Syed Mohd Faisal

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.

Brain tumor

Tumor progression

10.3389/fphar.2021.680021

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Citations (59)

Murine brain tumor microenvironment immunophenotyping using mass cytometry

STAR Protocols (2022)

Brandon L. McClellan Mahmoud S. Alghamri Rohit Thalla Pedro R. Löwenstein María G. Castro

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).

Mass cytometry

Immunophenotyping

Cytometry

10.1016/j.xpro.2022.101357

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Citations (1)

TAMI-52. G-CSF SECRETED BY EPIGENETICALLY REPROGRAMMED MUTANT IDH1 GLIOMA STEM CELLS, REVERSES THE MYELOID CELLS’-MEDIATED IMMUNOSUPPRESSIVE TUMOR MICROENVIRONMENT

Neuro-Oncology (2020)

Mahmoud S. Alghamri Ruthvik Avvari Rohit Thalla Li Zhang Maria Ventosa

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.

Reprogramming

Isocitrate dehydrogenase

10.1093/neuonc/noaa215.939

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Systemic delivery of a CXCR4-CXCL12 signaling inhibitor encapsulated in synthetic protein nanoparticles for glioma immunotherapy

bioRxiv (Cold Spring Harbor Laboratory) (2021)

Mahmoud S. Alghamri Kaushik Banerjee Anzar Mujeeb Ayman Taher Rohit Thalla

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 abstract Immunological 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.

10.1101/2021.08.27.457953

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G-CSF secreted by mutant IDH1 glioma stem cells abolishes myeloid cell immunosuppression and enhances the efficacy of immunotherapy

Science Advances (2021)

Mahmoud S. Alghamri Brandon L. McClellan Ruthvik Avvari Rohit Thalla Stephen V. Carney

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.

Reprogramming

Granulopoiesis

Myelopoiesis

10.1126/sciadv.abh3243

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Citations (72)

Systemic Delivery of an Adjuvant CXCR4–CXCL12 Signaling Inhibitor Encapsulated in Synthetic Protein Nanoparticles for Glioma Immunotherapy

ACS Nano (2022)

Mahmoud S. Alghamri Kaushik Banerjee Anzar Mujeeb Ava Mauser Ayman Taher

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 has poor pharmacokinetic properties, and unfavorable bioavailability has 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.

10.1021/acsnano.1c07492

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Tumor Mutational Burden Predicts Survival In Patients With Low Grade Gliomas Expressing Mutated IDH1

medRxiv (Cold Spring Harbor Laboratory) (2020)

Mahmoud S. Alghamri Rohit Thalla Ruthvik Avvari Ali Dabaja Ayman Taher

ABSTRACT Gliomas are the most common primary brain tumors. High Grade Gliomas have a median survival of 18 months, while Low Grade Gliomas (LGG) have a median survival of ∼7.3 years. Seventy-six percent of patients with LGG express mutated isocitrate dehydrogenase (mIDH1) enzyme (IDH1 R132H ). Survival of these patients ranges from 1-15 years, and tumor mutational burden ranges from 8 to 447 total somatic mutations per tumor. We tested the hypothesis that the tumor mutational burden would predict survival of patients with tumors bearing mIDH1 R132H . 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 Chinese Glioma Genome Atlas. High tumor mutational burden negatively correlates with survival of patients with LGG harboring IDH1 R132H (p<0.0001). This effect was significant for both Oligodendroglioma and Astrocytoma LGG- m IDH1 patients. In the TCGA data, median survival of the high mutational burden group was 76 months, while in the low mutational burden group it was 136 months; p<0.0001. There was no differential representation of frequently mutated genes (e.g., TP53, ATRX, CIC, FUBP ) in either group. Gene set enrichment analysis revealed an enrichment in Gene Ontologies related to Cell cycle, DNA damage response in high vs low tumor mutational burden. Finally, we identified a 19 gene signature that predicts survival for patients from both databases. In summary, we demonstrate that tumor mutational burden is a powerful, robust, and clinically relevant prognostic factor of median survival in mIDH1 patients.

Isocitrate dehydrogenase

ATRX

IDH2

10.1101/2020.01.20.20016766

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Active STAT3 Prevents Selinexor-Induced Caspase-Independent Apoptosis in Multiple Myeloma

Blood (2023)

Ryan Mack Mark Sellin Stephanie Berg Rohit Thalla Kanak Joshi

Regimen

10.1182/blood-2023-190030

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Citations (1)

G-CSF Secreted by Epigenetically Reprogrammed Mutant IDH1 Glioma Stem Cells Reverses the Myeloid Cells’-Mediated Immunosuppressive Tumor Microenvironment

bioRxiv (Cold Spring Harbor Laboratory) (2020)

Mahmoud S. Alghamri Ruthvik Avvari Rohit Thalla Neha Kamran Li Zhang

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. SIGNIFICANCE mIDH1 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.

ATRX

Reprogramming

Myelopoiesis

Isocitrate dehydrogenase

10.1101/2020.07.22.215954

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Citations (3)

Tumor mutational burden predicts survival in patients with low-grade gliomas expressing mutated IDH1

Neuro-Oncology Advances (2020)

Mahmoud S. Alghamri Rohit Thalla Ruthvik Avvari Ali Dabaja Ayman Taher

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.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.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.we demonstrate that tumor mutational burden is a powerful, robust, and clinically relevant prognostic factor of MS in mIDH patients.

Isocitrate dehydrogenase

ATRX

IDH2

Brain tumor

10.1093/noajnl/vdaa042

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Citations (20)