Glioblastoma are rapidly proliferating brain tumors in which hypoxia is readily recognizable, as indicated by focal or extensive necrosis and vascular proliferation, two independent diagnostic ...criteria for glioblastoma. Gene expression profiling of glioblastoma revealed a gene expression signature associated with hypoxia-regulated genes. The correlated gene set emerging from unsupervised analysis comprised known hypoxia-inducible genes involved in angiogenesis and inflammation such as VEGF and BIRC3, respectively. The relationship between hypoxia-modulated angiogenic genes and inflammatory genes was associated with outcome in our cohort of glioblastoma patients treated within prospective clinical trials of combined chemoradiotherapy. The hypoxia regulation of several new genes comprised in this cluster including ZNF395, TNFAIP3, and TREM1 was experimentally confirmed in glioma cell lines and primary monocytes exposed to hypoxia in vitro. Interestingly, the cluster seems to characterize differential response of tumor cells, stromal cells and the macrophage/microglia compartment to hypoxic conditions. Most genes classically associated with the inflammatory compartment are part of the NF-kappaB signaling pathway including TNFAIP3 and BIRC3 that have been shown to be involved in resistance to chemotherapy.Our results associate hypoxia-driven tumor response with inflammation in glioblastoma, hence underlining the importance of tumor-host interaction involving the inflammatory compartment.
Glioblastomas (GBMs) are complex ecosystems composed of highly multifaceted tumor and myeloid cells capable of responding to different environmental pressures, including therapies. Recent studies ...have uncovered the diverse phenotypical identities of brain-populating myeloid cells. Differences in the immune proportions and phenotypes within tumors seem to be dictated by molecular features of glioma cells. Furthermore, increasing evidence underscores the significance of interactions between myeloid cells and glioma cells that allow them to evolve in a synergistic fashion to sustain tumor growth. In this review, we revisit the current understanding of glioma-infiltrating myeloid cells and their dialogue with tumor cells in consideration of their increasing recognition in response and resistance to immunotherapies as well as the immune impact of the current chemoradiotherapy used to treat gliomas.
The epidermal growth factor receptor (EGFR) is over expressed in approximately 50-60% of glioblastoma (GBM) tumors, and the most common EGFR mutant, EGFRvIII, is expressed in 24-67% of cases. This ...study was designed to address whether over expressed EGFR or EGFRvIII is an actual independent prognostic indicator of overall survival in a uniform body of patients in whom gross total surgical resection (GTR; > or = 95% resection) was not attempted or achieved.
Biopsed or partially/subtotally resected GBM patients (N = 54) underwent adjuvant conformal radiation and chemotherapy. Their EGFR and EGFRvIII status was determined by immunohistochemistry and Kaplan-Meier estimates of overall survival were obtained.
In our study of GBM patients with less than GTR, 42.6% (n = 23) failed to express EGFR, 25.9% (n = 14) had over expression of the wild-type EGFR only and 31.5 % (n = 17) expressed the EGFRvIII. Patients within groups expressing the EGFR, EGFRvIII, or lacking EGFR expression did not differ in age, Karnofsky Performance Scale (KPS) score, extent of tumor resection. They all had received postoperative radiation and chemotherapy. The median overall survival times for patients with tumors having no EGFR expression, over expressed EGFR only, or EGFRvIII were 12.3 (95% CI, 8.04-16.56), 11.03 (95% CI, 10.18-11.89) and 14.07 (95% CI, 7.39-20.74) months, respectively, log rank test p > 0.05). Patients with tumors that over expressed the EGFR and EGFRvIII were more likely to present with ependymal spread, 21.4% and 35.3% respectively, compared to those patients whose GBM failed to express either marker, 13.0%, although the difference was not statistically significant. There was no significant difference in multifocal disease or gliomatosis cerebri among EGFR expression groups.
The over expressed wild-type EGFR and EGFRvIII are not independent predictors of median overall survival in the cohort of patients who did not undergo extensive tumor resection.
Introduction
Opening of the blood–brain barrier (BBB) by pulsed low intensity ultrasound has been developed during the last decade and is now recognized as a safe technique to transiently and ...repeatedly open the BBB. This non- or minimally invasive technique allows for a targeted and uniform dispersal of a wide range of therapeutic substances throughout the brain, including immune cells and antibodies.
Methods
In this review article, we summarize pre-clinical studies that have used BBB-opening by pulsed low intensity ultrasound to enhance the delivery of immune therapeutics and effector cell populations, as well as several recent clinical studies that have been initiated. Based on this analysis, we propose immune therapeutic strategies that are most likely to benefit from this strategy. The literature review and trial data research were performed using Medline/Pubmed databases and clinical trial registry
www.clinicaltrials.gov
. The reference lists of all included articles were searched for additional studies.
Results
A wide range of immune therapeutic agents, including small molecular weight drugs, antibodies or NK cells, have been safely and efficiently delivered to the brain with pulsed low intensity ultrasound in preclinical models, and both tumor control and increased survival have been demonstrated in different types of brain tumor models in rodents. Ultrasound-induced BBB disruption may also stimulate innate and cellular immune responses.
Conclusions
Ultrasound BBB opening has just recently entered clinical trials with encouraging results, and the association of this strategy with immune therapeutics creates a new field of brain tumor treatment.
Glioblastoma multiforme (GBM) is a lethal cancer that responds poorly to radiotherapy and chemotherapy. Glioma cancer-initiating
cells have been shown to recapitulate the characteristic features of ...GBM and mediate chemotherapy and radiation resistance.
However, it is unknown whether the cancer-initiating cells contribute to the profound immune suppression in GBM patients.
Recent studies have found that the activated form of signal transducer and activator of transcription 3 (STAT3) is a key mediator
in GBM immunosuppression. We isolated and generated CD133+ cancer-initiating single colonies from GBM patients and investigated
their immune-suppressive properties. We found that the cancer-initiating cells inhibited T-cell proliferation and activation,
induced regulatory T cells, and triggered T-cell apoptosis. The STAT3 pathway is constitutively active in these clones and
the immunosuppressive properties were markedly diminished when the STAT3 pathway was blocked in the cancer-initiating cells.
These findings indicate that cancer-initiating cells contribute to the immune evasion of GBM and that blockade of the STAT3
pathway has therapeutic potential. Mol Cancer Ther; 9(1); 67–78
Seizures are a frequent complication of adult-type diffuse gliomas, and are often difficult to control with medications. Gliomas with mutations in isocitrate dehydrogenase 1 or 2 (IDHmut) are more ...likely than IDH-wild type (IDHwt) gliomas to cause seizures as part of their initial clinical presentation. However, whether IDHmut is also associated with seizures during the remaining disease course, and whether IDHmut inhibitors can reduce seizure risk, are unclear. Clinical multivariable analyses showed that preoperative seizures, glioma location, extent of resection, and glioma molecular subtype (including IDHmut status) all contributed to postoperative seizure risk in adult-type diffuse glioma patients, and that postoperative seizures were often associated with tumor recurrence. Experimentally, the metabolic product of IDHmut, d-2-hydroxyglutarate, rapidly synchronized neuronal spike firing in a seizure-like manner, but only when non-neoplastic glial cells were present. In vitro and in vivo models recapitulated IDHmut glioma-associated seizures, and IDHmut inhibitors currently being evaluated in glioma clinical trials inhibited seizures in those models, independent of their effects on glioma growth. These data show that postoperative seizure risk in adult-type diffuse gliomas varies in large part by molecular subtype, and that IDHmut inhibitors could play a key role in mitigating such risk in IDHmut glioma patients.
Although tissue-resident memory T (T
) cells specific for previously encountered pathogens have been characterized, the induction and recruitment of brain T
cells following immune therapy has not ...been observed in the context of glioblastoma. Here, we show that T cells expressing fibrinogen-like 2 (FGL2)-specific single-chain variable fragments (T-αFGL2) can induce tumor-specific CD8
T
cells that prevent glioblastoma recurrence. These CD8
T
cells display a highly expanded T cell receptor repertoire distinct from that found in peripheral tissue. When adoptively transferred to the brains of either immunocompetent or T cell-deficient naïve mice, these CD8
T
cells reject glioma cells. Mechanistically, T-αFGL2 cell treatment increased the number of CD69
CD8
brain-resident memory T cells in tumor-bearing mice via a CXCL9/10 and CXCR3 chemokine axis. These findings suggest that tumor-specific brain-resident CD8
T
cells may have promising implications for the prevention of brain tumor recurrence.
Purpose: Glioblastoma multiforme is a lethal cancer that responds poorly to therapy. Glioblastoma multiforme cancer-initiating cells
have been shown to mediate resistance to both chemotherapy and ...radiation; however, it is unknown to what extent these cells
contribute to the profound immunosuppression in glioblastoma multiforme patients and if strategies that alter their differentiation
state can reduce this immunosuppression.
Experimental Design: We isolated a subpopulation of cells from glioblastoma multiforme that possessed the capacity for self-renewal, formed neurospheres
in vitro , were capable of pluripotent differentiation, and could initiate tumors in vivo . The immune phenotype of these cells was characterized including the elaboration of immunosuppressive cytokines and chemokines
by ELISA. Functional immunosuppressive properties were characterized based on the inhibition of T-cell proliferation and effector
responses, triggering of T-cell apoptosis, and induction of FoxP3 + regulatory T cells. On altering their differentiation state, the immunosuppressive phenotype and functional assays were reevaluated.
Results: We found that the cancer-initiating cells markedly inhibited T-cell proliferation and activation, induced regulatory T cells,
and triggered T-cell apoptosis that was mediated by B7-H1 and soluble Galectin-3. These immunosuppressive properties were
diminished on altering the differentiation of the cancer-initiating cells.
Conclusion: Cancer-initiating cells contribute to tumor evasion of the immunosurveillance and approaches that alter the differentiation
state may have immunotherapeutic potential. Clin Cancer Res; 16(2); 461–73
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