[Show abstract][Hide abstract] ABSTRACT: INTRODUCTION: Tumorreleased exosomes have pleiotropic functions in promoting autocrine signaling to distant cells. Elucidating the mechanistic modulation of the immune system by these exosomes provides insights into potential biomarkers for detection, recurrence and response and identifies potential new therapeutic targets.
[Show abstract][Hide abstract] ABSTRACT: Background:
Fibrinogen-like protein 2 (FGL2) may promote glioblastoma multiforme (GBM) cancer development by inducing multiple immune-suppression mechanisms.
The biological significance of FGL2 expression was assessed using the The Cancer Genome Atlast (TCGA) glioma database and tumor lysates analysis. The therapeutic effects of an anti-Fgl2 antibody and the role of immune suppression regulation by Fgl2 were determined in immune-competent, NOD-scid IL2Rgammanull (NSG), and FcɣRIIB-/- mice (n = 3-18 per group). Data were analyzed with two-way analysis of variance, log-rank survival analysis, and Pearson correlation. All statistical tests were two-sided.
In low-grade gliomas, 72.5% of patients maintained two copies of the FGL2 gene, whereas 83.8% of GBM patients had gene amplification or copy gain. Patients with high levels of FGL2 mRNA in glioma tissues had a lower overall survival (P = .009). Protein levels of FGL2 in GBM lysates were higher relative to low-grade glioma lysates (11.48±5.75ng/mg vs 3.96±1.01ng/mg, P = .003). In GL261 mice treated with an anti-FGL2 antibody, median survival was 27 days compared with only 17 days for mice treated with an isotype control antibody (P = .01). The anti-FGL2 antibody treatment reduced CD39(+) Tregs, M2 macrophages, programmed cell death protein 1 (PD-1), and myeloid-derived suppressor cells (MDSCs). FGL2-induced increases in M2, CD39, and PD-1 were ablated in FcɣRIIB-/- mice.
FGL2 augments glioma immunosuppression by increasing the expression levels of PD-1 and CD39, expanding the frequency of tumor-supportive M2 macrophages via the FcγRIIB pathway, and enhancing the number of MDSCs and CD39(+) regulatory T cells. Collectively, these results show that FGL2 functions as a key immune-suppressive modulator and has potential as an immunotherapeutic target for treating GBM.
JNCI Journal of the National Cancer Institute 05/2015; 107(8). DOI:10.1093/jnci/djv137 · 12.58 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The role of tumor-induced immune modulation in cancer progression is currently a focus of investigation. The signal transducer and activator of transcription 3 (STAT3) is an established molecular hub of immunosuppression, and its signaling pathways are classically overactivated within malignancies. This article will review STAT3 operational mechanisms within the immune system and the tumor microenvironment, with a focus on therapeutic strategies that may impact outcomes for patients with cancer.
Journal of Neuro-Oncology 02/2015; 123(3). DOI:10.1007/s11060-015-1731-3 · 3.07 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Immunotherapeutic approaches to cancer have shown remarkable promise. A critical barrier to successfully executing such immune-mediated
interventions is the selection of safe yet immunogenic targets. As patient deaths have occurred when tumor-associated antigens
shared by normal tissue have been targeted by strong cellular immunotherapeutic platforms, route of delivery, target selection
and the immune-mediated approach undertaken must work together to maximize efficacy with safety. Selected tumor-specific targets
can spare potential toxicity to normal tissue; however, they are far less common than tumor-associated antigens and may not
be present on all patients. In the context of immunotherapy for high-grade glioma, 2 of the most prominently studied antigens
are the tumor-associated epidermal growth factor receptor and its tumor-specific genetic deletion variant III. In this review,
we will summarize the immune-mediated strategies employed against these targets as well as the caveats particular to these
[Show abstract][Hide abstract] ABSTRACT: Fibrinogen-like protein 2 (Fgl2), a member of the fibrinogen family, can be expressed as a membrane-associated protein with coagulation activity or in a secreted form possessing unique immune suppressive functions. The biological importance of Fgl2 is evident within viral-induced fibrin depositing inflammatory diseases and malignancies and provides a compelling rationale for Fgl2 expression to not only be considered as a disease biomarker but also as a therapeutic target. This article will provide a comprehensive review of the currently known biological properties of Fgl2 and clarifies future scientific directives.
International Reviews Of Immunology 09/2014; DOI:10.3109/08830185.2014.956360 · 4.10 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Background:
The immune therapeutic potential of microRNAs (miRNAs) in the context of tumor-mediated immune suppression has not been previously described for monocyte-derived glioma-associated macrophages, which are the largest infiltrating immune cell population in glioblastomas and facilitate gliomagenesis.
An miRNA microarray was used to compare expression profiles between human glioblastoma-infiltrating macrophages and matched peripheral monocytes. The effects of miR-142-3p on phenotype and function of proinflammatory M1 and immunosuppressive M2 macrophages were determined. The therapeutic effect of miR-142-3p was ascertained in immune-competent C57BL/6J mice harboring intracerebral GL261 gliomas and in genetically engineered Ntv-a mice bearing high-grade gliomas. Student t test was used to evaluate the differences between ex vivo datasets. Survival was analyzed with the log-rank test and tumor sizes with linear mixed models and F test. All statistical tests were two-sided.
miR-142-3p was the most downregulated miRNA (approximately 4.95-fold) in glioblastoma-infiltrating macrophages. M2 macrophages had lower miR-142-3p expression relative to M1 macrophages (P = .03). Overexpression of miR-142-3p in M2 macrophages induced selective modulation of transforming growth factor beta receptor 1, which led to subsequent preferential apoptosis in the M2 subset (P = .01). In vivo miR-142-3p administration resulted in glioma growth inhibition (P = .03, n = 5) and extended median survival (miR-142-3p-treated C57BL/6J mice vs scramble control: 31 days vs 23.5 days, P = .03, n = 10; miR-142-3p treated Ntv-a mice vs scramble control: 32 days vs 24 days, P = .03, n = 9), with an associated decrease in infiltrating macrophages (R (2) = .303).
These data indicate a unique role of miR-142-3p in glioma immunity by modulating M2 macrophages through the transforming growth factor beta signaling pathway.
JNCI Journal of the National Cancer Institute 08/2014; 106(8). DOI:10.1093/jnci/dju162 · 12.58 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Despite the recent successes of using immune modulatory antibodies in cancer patients, autoimmune pathologies resulting from the activation of self self-reactive T cells preclude the dose escalations necessary to fully exploit their therapeutic potential. To reduce the observed and expected toxicities associated with immune modulation, here we describe a clinically feasible and broadly applicable approach to limit immune costimulation to the disseminated tumor lesions of the patient whereby an agonistic 4-1BB oligonucleotide aptamer is targeted to the tumor stroma by conjugation to an aptamer that binds to a broadly expressed stromal product, vascular endothelial growth factor (VEGF). The approach was predicated on the premise that by targeting the costimulatory ligands to products secreted into the tumor stroma the T cells will be costimulated prior to their engagement of the MHC/peptide complex on the tumor cell, thereby obviating the need to target the costimulatory ligands to non-internalizing cell cell-surface products expressed on the tumor cells. Underscoring the potency of stroma stroma-targeted costimulation and the broad spectrum of tumors secreting VEGF, in preclinical murine tumor models systemic administration of the VEGF VEGF-targeted 4-1BB aptamer conjugates engendered potent antitumor immunity against multiple unrelated tumors in subcutaneous, post post-surgical lung metastasis, methylcholantrene-induced fibrosarcoma, and oncogene-induced autochthonous glioma models, and exhibited a superior therapeutic index compared to non-targeted administration of an agonistic 4-1BB antibody or 4-1BB aptamer.
[Show abstract][Hide abstract] ABSTRACT: Despite extensive study, few therapeutic targets have been identified for glioblastoma (GBM). Here we show that patient-derived glioma sphere cultures (GSCs) that resemble either the proneural (PN) or mesenchymal (MES) transcriptomal subtypes differ significantly in their biological characteristics. Moreover, we found that a subset of the PN GSCs undergoes differentiation to a MES state in a TNF-a/ NF-kB-dependent manner with an associated enrichment of CD44 subpopulations and radioresistant phenotypes. We present data to suggest that the tumor microenvironment cell types such as macro-phages/microglia may play an integral role in this process. We further show that the MES signature, CD44 expression, and NF-kB activation correlate with poor radiation response and shorter survival in patients with GBM. Significance In this study, we characterize plasticity between the proneural (PN) and mesenchymal (MES) transcriptome signatures observed in glioblastoma (GBM). Specifically, we show that PN glioma sphere cultures (GSCs) can be induced to a MES state with an associated enrichment of CD44 expressing cells and a gain of radioresistance, in an NF-kB-dependent fashion. Newly diagnosed GBM samples show a direct correlation among radiation response, higher MES metagene, CD44 expres-sion, and NF-kB activation, and we propose macrophages/microglia as a potential microenvironmental component that can regulate this transition. Our results reveal a mechanistic link between transcriptome plasticity, radiation resistance, and NF-kB signaling. Inhibition of NF-kB activation can directly affect radioresistance and presents an attractive therapeutic target for GBM.
Cancer Cell 09/2013; 24:331-346. · 23.52 Impact Factor