The immune checkpoints, CTLA-4 and PD-1, are negative regulators of T cell activation and are inducers of FoxP3+ Tregs. Monoclonal antibody therapy to each has demonstrated tumor regression in ...clinical trials and potent therapeutic synergy has been observed when used in combination. MicroRNAs (miRs) have been shown to modulate gene transcripts involved in tumorigenesis and can target tumor-mediated immune suppression. On the basis of differential miRNA gene expression libraries from glioblastoma patients, miR-138 was identified as a top down regulated candidate. On glioma tumor microarrays, miR-138 expression is heterogeneous among the various grades and pathologies. Target binding algorithms predicted that miR-138 could bind CTLA-4 and PD-1. Transfection of human CD4+ T cells with miR-138 suppressed CTLA-4-, PD-1-, and FoxP3- expression in vitro. Treatment of established subcutaneous GL261 murine glioma cells in immune competent C57BL/6 mice with miR-138 or scramble control administered intravenously demonstrated that gliomas started to shrink as soon as miR-138 was administered. Moreover, the gliomas continued to regress even after miR-138 treatment was discontinued. In contrast, tumors kept growing aggressively in scramble miRNA-treated and untreated tumor-bearing mice groups. Furthermore, in C57BL/6 mice with established intracerebral GL261 treated with i.v. administered miR-138, median survival was 33.5 days relative to mice treated with scramble control with a median survival of 23.5 days (P=0.011). Intravenous treatment of mice with established intracerebral gliomas with miR-138 relative to the scramble control reduced the relative incidence of Tregs by 51% (P=0.03) within the glioma microenvironment. Formulation equivalency studies in vivo indicate that DOTAP causes rapid translocation of miRNAs into the peripheral blood compartment indicating that miR-138 may have rapid translational potential as a novel immunotherapeutic agent for neoplasms.
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 (Tregs) 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 GBMs’ immune evasion and that blockade of the STAT3 pathway has therapeutic potential.
The activator protein (AP)-2alpha transcription factor plays a crucial role in the progression of several human tumors, including malignant melanoma, prostate, and breast cancer. Loss of AP-2alpha ...results in deregulation of several genes with AP-2alpha binding motifs such as E-cadherin, p21WAF1, MMP-2, MCAM/MUC18, VEGF, and c-KIT. The purpose of our study was to determine AP-2alpha expression distribution among grades of gliomas and any possible effect on prognosis.
A tissue microarray was assembled from all surgical glioma cases with available tissue samples at M.D. Anderson Cancer Center since 1986 to include 72 glioblastomas, 49 anaplastic astrocytomas, 9 low-grade astrocytoma, 37 oligodendrogliomas, 37 anaplastic oligodendrogliomas, 15 mixed oligoastrocytomas, 20 anaplastic mixed oligoastrocytomas, and 7 gliosarcomas. The microarray included normal brain tissue, and AP-2alpha expression was determined by immunohistochemistry.
AP-2alpha expression was lost on 99% (P < 0.001) and 98% (P < 0.001) of glioblastomas and anaplastic astrocytomas, respectively, compared with grade 2 astrocytomas and normal brain, all of which (100%) maintained expression of AP-2alpha. The loss of AP-2alpha was a negative prognostic indicator within the overall category of gliomas by univariate analysis (rate ratio, 4.30; 95% confidence interval, 2.60-7.10; P < 0.001). However, there was no significant effect of loss of AP-2alpha expression on survival observed after adjustment for patient age, Karnofsky Performance Scale score, tumor grade, and extent of resection (rate ratio, 1.2; 95% confidence interval, 0.6-2.2; P = 0.6).
AP-2alpha expression correlates inversely with glioma grade, suggesting a direct role in glioma tumorigenicity, possibly through subsequent deregulation of target genes. Of all the previously characterized markers of progression, the loss of AP-2alpha would be the most common (96.2%) molecular marker as an astrocytic tumor evolves from grade 2 to 3.
Abstract
OBJECTIVE
Intraoperative localization of cortical areas for motor and language function has been advocated to minimize postoperative neurological deficits. We report herein the results of a ...retrospective study of cortical mapping and subsequent clinical outcomes in a large series of patients.
METHODS
Patients with intracerebral tumors near and/or within eloquent cortices (n = 309) were clinically evaluated before surgery, immediately after, and 1 month and 3 months after surgery. Craniotomy was tailored to encompass tumor plus adjacent areas presumed to contain eloquent cortex. Intraoperative cortical stimulation for language, motor, and/or sensory function was performed in all patients to safely maximize surgical resection.
RESULTS
A gross total resection (≥95%) was obtained in 64%, and a resection of 85% or more was obtained in 77% of the procedures. Eloquent areas were identified in 65% of cases, and in that group, worsened neurological deficits were observed in 21% of patients, whereas only 9% with negative mapping sustained such deficits (P < 0.01). Intraoperative neurological deficits occurred in 64 patients (21%); of these, 25 (39%) experienced worsened neurological outcome at 1 month, whereas only 27 of 245 patients (11%) without intraoperative changes had such outcomes (P < 0.001). At 1 month, 83% overall showed improved or stable neurological status, whereas 17% had new or worse deficits; however, at 3 months, 7% of patients had a persistent neurological deficit. Extent of resection less than 95% also predicted worsening of neurological status (P < 0.025).
CONCLUSION
Negative mapping of eloquent areas provides a safe margin for surgical resection with a low incidence of neurological deficits. However, identification of eloquent areas not only failed to eliminate but rather increased the risk of postoperative deficits, likely indicating close proximity of functional cortex to tumor.
Abstract
Venous thromboembolism (VTE) is a common paraneoplastic complication in patients with adult-type diffuse gliomas. VTE greatly diminishes quality-of-life, and can even be life-threatening. ...While effective VTE prediction models exist for other cancers, those models do not work for gliomas. Thus, there are no standard guidelines for thromboprophylaxis in glioma patients. To address this deficiency, arterial blood, tumor tissue, and comprehensive clinical-pathologic data (including next generation sequencing) were obtained from 258 newly diagnosed WHO grade 2-4 adult-type diffuse glioma patients at Northwestern Memorial Hospital. Forty-six out of 258 grade 2-4 glioma patients (17.8%) experienced a subsequent VTE. Intratumoral expression of two proteins that have been associated with VTE risk in other cancers, thromboplastin and podoplanin, was higher in IDH wild-type than IDH mutant gliomas. Tissue expression of both markers was associated with increased VTE risk, but in the circulation, only thromboplastin positively correlated with VTE. LASSO time-to-event analysis showed that older patient age, elevated body mass index, elevated WBC count, hypertension, a preoperative history of VTE, asthma, and higher WHO grade predicted increased postoperative VTE risk, whereas hypothyroidism, IDH mutation, and MGMT promoter methylation were negative risk factors. Together, these 10 variables generated a receiver operating characteristic curve for 3, 6, 9, and 12 months from original surgery resulting in estimated AUC value of 0.82 in the Northwestern discovery cohort, 0.72 in the UCLA validation cohort (N=68), and 0.68 in the Duke validation cohort (N=157). We created an online prediction tool based on this model, which estimates VTE risk up to 1 year from original surgery. To the best of our knowledge, this is the first externally validated VTE risk prediction tool designed specifically for adult-type diffuse glioma patients. This tool, based on readily obtainable information, provides treating physicians with more objective risk estimates on which to base thromboprophylaxis decision-making.
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