Biology subjects

Mujeeb, A. A.

Publications and source records attributed to Mujeeb, A. A..

7 recordsLinked to original sources

bioRxiv2026

Targeting NF-κB epigenetic activation and DNA repair deficiency in G34-mutant pediatric diffuse hemispheric glioma with nanoparticles combining PARP inhibition and immune stimulation mediated by CpG dinucleotides

Diffuse hemispheric gliomas (DHGs) are highly aggressive and infiltrative CNS tumors that are refringent to treatment, and with a 5-year overall survival of around 20%. A fraction of DHGs is driven by mutations in the histones H3.1 and H3.3. In this study, we demonstrate that the expression of histone H3.3 glycine 34 to arginine mutations (H3.3-G34R) result in the epigenetic and transcriptional activation of the NF-{kappa}B signaling pathway in DHG. To target this vulnerability, we designed high density lipoprotein (HDL) nanoparticles loaded with unmethylated CpG dinucleotides, which mimic the immune stimulatory activity of bacterial DNA. CpG are recognized by Toll-like receptor 9 (TLR9), activating the NF-{kappa}B signaling. The CpG-mediated NF-{kappa}B activation results in the release of immuno-stimulating cytokines that promote an antitumoral response. As we previously established that G34-mutant DHGs are characterized by DNA repair impairment, we combined CpG dinucleotides with a PARP (poly (ADP-ribose) polymerase) inhibitor, olaparib, in the HDL nanoparticles.

cancer biology↗

bioRxiv2026

MIF-mediated reprogramming of myeloid lineage within the glioma tumor microenvironment impacts the efficacy of immune stimulatory gene therapy

Gliomas with mutant isocitrate dehydrogenase 1 (mIDH1) represent a distinct subgroup of brain tumors characterized by unique metabolic and immunological profiles compared to wildtype IDH1 (wtIDH1) gliomas. Despite recent progress, the cellular mechanisms underlying tumor progression and immune modulation in these subtypes remain poorly understood. In this study, we employed single-cell RNA sequencing (scRNA-seq) to characterize the cellular heterogeneity of wtIDH1 and mIDH1 gliomas, with a particular focus on myeloid cell populations. Our analyses revealed a marked reduction of monocyte-derived tumor-associated macrophages (Mo-TAMs) and lower expression of macrophage migration inhibitory factor (MIF) in mIDH1 gliomas, which was attributable to epigenetic reprogramming. Mechanistic studies using MIF and CD74 knockout mice demonstrated that the MIF-CD74 axis plays a crucial role in regulating the glioma immune microenvironment, thereby driving tumor growth and progression. Importantly, the combination of immune-stimulatory gene therapy (HSV1-thymidine kinase/Fms-like tyrosine kinase 3 ligand; TK/Flt3L) with MIF inhibition significantly extended survival in models of wtIDH1 glioma. These findings highlight the therapeutic potential of targeting the MIF-CD74 pathway and underscore the importance of integrating immunomodulatory strategies for the treatment of glioma. HighlightsO_LIMutant IDH1 gliomas exhibit fewer Mo-TAMs and increased Mg-TAMs C_LIO_LIMutant IDH1 gliomas have less MIF expression via epigenetic reprogramming. C_LIO_LIMesenchymal wtIDH1 glioma cells are main source of MIF. C_LIO_LIMIF inhibition plus immune stimulatory gene therapy extends survival wtIDH1 glioma. C_LI

cancer biology↗

bioRxiv2025

Reprogramming the Immune Suppressive Tumor Microenvironment in Glioma Enhances the Efficacy of Immune-Mediated Gene Therapy

Gliomas account for ~80% of primary malignant brain tumors. Many CNS WHO grade 2-3 and some grade 4 gliomas harbor mutant isocitrate dehydrogenase 1 (mIDH1), which causes a gain of function mutation (IDH1 R132H) leading to the production of 2-hydroxyglutarate (2HG). Mutant IDH1-induced 2HG, through epigenetic reprogramming elicits an immune-permissive tumor microenvironment (TME). An immunosuppressive mechanism in the glioma TME involves adenosine production via the ectoenzyme CD73. This study investigates mIDH1s influence on CD73 expression and adenosine levels. We demonstrate that mIDH1 glioma cells exhibit reduced CD73 expression, driven by DNA hypermethylation, leading to reduced adenosine levels. Since wtIDH1 gliomas have high CD73 expression, we evaluated CD73 blockade as an immunotherapy target. We show that CD73 inhibition used as monotherapy, did not improve survival in wtIDH1 glioma-bearing mice. However, when combined with immune-stimulatory Ad-TK (adenoviral vectors encoding herpes simplex virus thymidine kinase) and Ad-Flt3L (adenoviral vectors encoding FMS-like tyrosine kinase 3 ligand) gene therapy, CD73 blockade significantly enhanced therapeutic efficacy and increased anti-glioma effector T cell activity. These findings reveal that CD73 inhibition used in combination with immune stimulatory Ad-TK/Ad-Flt3L gene therapy may be an effective treatment for wtIDH1 gliomas, which could be readily translated to the clinical arena.

cancer biology↗

bioRxiv2025

HDL Nanodiscs Loaded with Liver X Receptor Agonist Decreases Tumor Burden and Mediates Long-term Survival in Mouse Glioma Model

Glioblastoma multiforme (GBM) is highly aggressive primary brain tumor with a 5-year survival rate of 7%. Previous studies have shown that GBM tumors have a reduced capacity to produce cholesterol and instead depend on the uptake of cholesterol produced by astrocytes. To target cholesterol metabolism to induce cancer cell death, synthetic high-density lipoprotein (sHDL) nanodiscs delivering Liver-X-Receptor (LXR) agonists and CpG oligonucleotides for targeting GBM were investigated. LXR agonists synergize with sHDL nanodiscs by increasing the expression of the ABCA1 cholesterol CpG oligonucleotides are established adjuvants used in cancer immunotherapy that work through the toll-like receptor 9 pathway. In the present study, treatment with GW-CpG-sHDL nanodiscs increased the expression of cholesterol efflux transporters on murine GL261 cells leading to enhanced cholesterol removal. Experiments in GL261-tumor-bearing mice revealed combining GW-CpG-sHDL nanodiscs with radiation (IR) therapy significantly increases median survival compared to GW-CpG-sHDL or IR alone. Furthermore, 66% of long-term survivors from the GW-CpG-sHDL +IR treatment group showed no tumor tissue when rechallenged.

cancer biology↗

bioRxiv2024

CD200 depletion in glioma enhances antitumor immunity and induces tumor rejection

High-grade gliomas are a major health challenge with poor prognosis and high morbidity. Immune-checkpoint inhibitors (ICI) have emerged as promising therapeutic options for several malignancies yet show little efficacy against central nervous system (CNS) tumors. CD200 is a newly recognized immune checkpoint that modulates immune homeostasis. CD200 protein is expressed by a variety of cells, including immune cells and stromal cells, and is overexpressed by many tumors. The shedding of CD200 from tumor cells can create an immunosuppressive environment that dampens anti-tumor immunity by modulating cytolytic activity and cytokine expression both within and outside the tumor microenvironment (TME). While it is well-accepted that CD200 induces a pro-tumorigenic environment through its ability to suppress the immune response, we sought to determine the role of glioma-specific expression of CD200. We show that CD200 is expressed across glioma types, is shed from tumor cells, and increases over time in the serum of patients undergoing immunotherapy. Using CD200 knockout (KO) glioma models, we demonstrated that glioma cell-derived CD200 promotes tumor growth in vivo and in vitro. Notably, CD200 KO gliomas are spontaneously rejected by their host, a process that required a fully functional immune system, including NK and T-cells. Moreover, we report that glioma-derived or brain-injected soluble CD200 contributes to the suppression of antigen-specific CD8 T-cells in the draining lymph nodes (dLNs). Our work provides new mechanistic insights regarding CD200-mediated immunosuppression by gliomas. Statement of significanceWe demonstrate mechanisms of the druggable glioma-derived CD200 checkpoint on tumor growth and immune suppression.

immunology↗

bioRxiv2024

Epigenetic Reprogramming of Autophagy Drives Mutant IDH1 Glioma Progression and Response to Radiation

Mutant isocitrate dehydrogenase 1 (mIDH1) exhibits a gain of function mutation enabling 2-hydroxyglutarate (2HG) production and epigenetic reprogramming. This leads to enhanced DNA-damage response and radioresistance in mIDH1 gliomas. RNA-seq and ChIP-seq data revealed that human and mouse mIDH1 glioma neurospheres have downregulated gene ontologies (GOs) related to mitochondrial metabolism and upregulated GOs related to autophagy. Decreased mitochondrial metabolism was accompanied by decreased glycolysis, rendering autophagy a source of energy in mIDH1 gliomas. Human and mouse mutant IDH1 glioma cells exhibited increased expression of pULK1-S555 and enhanced LC3 I/II conversion, indicating augmented autophagy. Additionally, scRNA-seq data from human mIDH1 astrocytoma patients samples showed decreased mitochondrial metabolism and increased autophagy. We further demonstrate that inhibiting autophagy in vivo by systemic administration of synthetic protein nanoparticles encapsulating siRNA targeting Atg7 sensitized mIDH1 glioma cells to radiation-induced cell death, resulting in tumor regression, long-term survival, and immunological memory. In summary, our work uncovered that autophagy is a critical pathway for survival in mIDH1 gliomas and by blocking this pathway we can elicit radiosensitivity in vitro in human and mouse mIDH1 glioma cells, and in vivo in genetically engineered mouse models. Our data also highlights that blocking autophagy has significant potential for clinical translation. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=102 SRC="FIGDIR/small/584091v2_ufig1.gif" ALT="Figure 1"> View larger version (32K): org.highwire.dtl.DTLVardef@111f4a9org.highwire.dtl.DTLVardef@1d5bb30org.highwire.dtl.DTLVardef@f467ecorg.highwire.dtl.DTLVardef@1d2e9b5_HPS_FORMAT_FIGEXP M_FIG O_FLOATNOGraphical Abstract:C_FLOATNO Our genetically engineered mIDH1 mouse glioma model harbors IDH1R132H in the context of ATRX and TP53 knockdown. The production of 2-HG elicited an epigenetic reprogramming associated with a disruption in mitochondrial activity and an enhancement of autophagy in mIDH1 glioma cells. Autophagy is a mechanism involved in cell homeostasis related with cell survival under energetic stress and DNA damage protection. Autophagy has been associated with radio resistance. The inhibition of autophagy thus radio sensitizes mIDH1 glioma cells and enhances survival of mIDH1 glioma-bearing mice, representing a novel therapeutic target for this glioma subtype with potential applicability in combined clinical strategies. C_FIG

cancer biology↗

bioRxiv2021

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

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 O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=141 SRC="FIGDIR/small/457953v1_ufig1.gif" ALT="Figure 1"> View larger version (48K): org.highwire.dtl.DTLVardef@17c9377org.highwire.dtl.DTLVardef@1b5a4dcorg.highwire.dtl.DTLVardef@5aa4eaorg.highwire.dtl.DTLVardef@1011a86_HPS_FORMAT_FIGEXP M_FIG 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. C_FIG

cell biology↗