RESUMO
PURPOSE: Gliomas are primary brain tumors with a life-limiting course of disease, and the last weeks of life are often characterized by neurological deficits that affect communication and personality. End-of-life treatment in this patient group therefore requires specific approaches. To date, little data is available on patients' and caregivers' needs and experiences in the last phase of the disease. METHODS: In this observational study, relatives of patients treated at the University Hospital Zurich, Switzerland and deceased 2015-2017 due to glioma progression were contacted to complete a structured questionnaire assessing caregivers experience within the last weeks of the disease. RESULTS: The survey was sent to 120 relatives of deceased patients with a glioma (WHO grades II-IV) (median patient age: 62 years; 73.8% male). Forty-three questionnaires were returned (37.7%). Approximately half of the patients were taken care of at home in the last 4 weeks of the disease, mainly with the assistance of in-home nursing care, of which eventually 14 patients (63.6%) died at home. While caregivers reported high satisfaction with medical and nursing care, psychological support was rated average to poor on a 10-point scale. Free comment fields were used widely, revealing open questions and needs of the relatives. CONCLUSIONS: This study illustrates the need for a more patient-centered end-of-life care including higher psychological support mechanisms, and a higher inclusion and consideration of relatives and caregivers into the care focus. Earlier discussion of end-of-life preferences could prevent hospitalizations in the last phase of life and could improve patients' and caregivers' quality of life.
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Neoplasias Encefálicas , Cuidadores/psicologia , Glioma , Assistência Terminal/psicologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias Encefálicas/psicologia , Neoplasias Encefálicas/terapia , Feminino , Glioma/psicologia , Glioma/terapia , Humanos , Masculino , Pessoa de Meia-Idade , Cuidados Paliativos/psicologia , Inquéritos e Questionários , Adulto JovemRESUMO
Glioblastoma is the most frequent malignant primary brain tumor. In a hierarchical tumor model, glioblastoma stem-like cells (GSC) play a major role in tumor initiation and maintenance as well as in therapy resistance and recurrence. Thus, targeting this cellular subset may be key to effective immunotherapy. Here, we present a mass spectrometry-based analysis of HLA-presented peptidomes of GSC and glioblastoma patient specimens. Based on the analysis of patient samples (n = 9) and GSC (n = 3), we performed comparative HLA peptidome profiling against a dataset of normal human tissues. Using this immunopeptidome-centric approach we could clearly delineate a subset of naturally presented, GSC-associated HLA ligands, which might serve as highly specific targets for T cell-based immunotherapy. In total, we identified 17 antigens represented by 41 different HLA ligands showing natural and exclusive presentation both on GSC and patient samples. Importantly, in vitro immunogenicity and antigen-specific target cell killing assays suggest these peptides to be epitopes of functional CD8+ T cell responses, thus rendering them prime candidates for antigen-specific immunotherapy of glioblastoma.
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Neoplasias Encefálicas/metabolismo , Glioblastoma/metabolismo , Antígenos HLA/metabolismo , Células-Tronco Neoplásicas/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Encéfalo/metabolismo , Encéfalo/patologia , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patologia , Neoplasias Encefálicas/terapia , Linfócitos T CD8-Positivos/metabolismo , Linhagem Celular Tumoral , Criança , Estudos de Coortes , Feminino , Glioblastoma/genética , Glioblastoma/patologia , Glioblastoma/terapia , Humanos , Imunoterapia/métodos , Isocitrato Desidrogenase/genética , Ligantes , Masculino , Pessoa de Meia-IdadeRESUMO
The purpose of the present study is to analyze the impact of intraoperative resection control modalities on overall survival (OS) and progression-free survival (PFS) following gross total resection (GTR) of glioblastoma. We analyzed data of 76 glioblastoma patients (30f, mean age 57.4 ± 11.6 years) operated at our institution between 2009 and 2012. Patients were only included if GTR was achieved as judged by early postoperative high-field MRI. Intraoperative technical resection control modalities comprised intraoperative ultrasound (ioUS, n = 48), intraoperative low-field MRI (ioMRI, n = 22), and a control group without either modality (n = 11). The primary endpoint of our study was OS, and the secondary endpoint was PFS-both analyzed in Kaplan-Meier plots and Cox proportional hazards models. Median OS in all 76 glioblastoma patients after GTR was 20.4 months (95 % confidence interval (CI) 18.5-29.0)-median OS in patients where GTR was achieved using ioUS was prolonged (21.9 months) compared to those without ioUS usage (18.8 months). A multiple Cox model adjusting for age, preop Karnofsky performance status, tumor volume, and the use of 5-aminolevulinic acid showed a beneficial effect of ioUS use, and the estimated hazard ratio was 0.63 (95 % CI 0.31-1.2, p = 0.18) in favor of ioUS, however not reaching statistical significance. A similar effect was found for PFS (hazard ratio 0.59, p = 0.072). GTR of glioblastoma performed with ioUS guidance was associated with prolonged OS and PFS. IoUS should be compared to other resection control devices in larger patient cohorts.
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Neoplasias Encefálicas/mortalidade , Neoplasias Encefálicas/cirurgia , Glioblastoma/mortalidade , Glioblastoma/cirurgia , Procedimentos Neurocirúrgicos , Intervalo Livre de Doença , Feminino , Glioblastoma/diagnóstico , Humanos , Avaliação de Estado de Karnofsky/estatística & dados numéricos , Masculino , Neoplasia Residual/mortalidade , Neoplasia Residual/patologia , Modelos de Riscos Proporcionais , Resultado do TratamentoRESUMO
Human glioblastomas may be hierarchically organized. Within this hierarchy, glioblastoma-initiating cells have been proposed to be more resistant to radiochemotherapy and responsible for recurrence. Here, established stem cell markers and stem cell attributed characteristics such as self-renewal capacity and tumorigenicity have been profiled in primary glioblastoma cultures to predict radiosensitivity. Furthermore, the sensitivity to radiotherapy of different subpopulations within a single primary glioblastoma culture was analyzed by a flow cytometric approach using Nestin, SRY (sex-determining region Y)-box 2 (SOX2) and glial fibrillary acidic protein. The protein expression of Nestin and SOX2 as well as the mRNA levels of Musashi1, L1 cell adhesion molecule, CD133, Nestin, and pleiomorphic adenoma gene-like 2 inversely correlated with radioresistance in regard to the clonogenic potential. Only CD44 protein expression correlated positively with radioresistance. In terms of proliferation, Nestin protein expression and Musashi1, pleiomorphic adenoma gene-like 2, and CD133 mRNA levels are inversely correlated with radioresistance. Higher expression of stem cell markers does not correlate with resistance to radiochemotherapy in the cancer genome atlas glioblastoma collective. SOX2 expressing subpopulations exist within single primary glioblastoma cultures. These subpopulations predominantly form the proliferative pool of the primary cultures and are sensitive to irradiation. Thus, profiling of established stem cell markers revealed a surprising result. Except CD44, the tested stem cell markers showed an inverse correlation between expression and radioresistance. Markers used to define glioma-initiating cells (GIC) are generally not defining a more resistant, but rather a more sensitive group of glioma cells. An exemption is CD44 expression. Also proliferation of the GIC culture itself was not systematically associated with radiosensitivity or - resistance, but a SOX-2 positive, proliferative subgroup within a GIC culture is showing the highest radiosensitivity.
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Biomarcadores Tumorais/biossíntese , Biomarcadores Tumorais/efeitos da radiação , Glioblastoma/radioterapia , Células-Tronco Neoplásicas/metabolismo , Células-Tronco Neoplásicas/efeitos da radiação , Animais , Feminino , Previsões , Glioblastoma/patologia , Humanos , Camundongos , Camundongos Nus , Radioterapia/métodos , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de Xenoenxerto/métodosRESUMO
The integrin antagonist cilengitide has been explored as an adjunct with anti-angiogenic properties to standard of care temozolomide chemoradiotherapy (TMZ/RT â TMZ) in newly diagnosed glioblastoma. Preclinical data as well as anecdotal clinical observations indicate that anti-angiogenic treatment may result in altered patterns of tumor progression. Using a standardized approach, we analyzed patterns of progression on MRI in 21 patients enrolled onto a phase 2 trial of cilengitide added to TMZ/RT â TMZ in newly diagnosed glioblastoma. Thirty patients from the experimental treatment arm of the EORTC/NCIC pivotal TMZ trial served as a reference. MRIcro software was used to map location and extent of initial preoperative and recurrent tumors on MRI of both groups into the same stereotaxic space which were then analyzed using an automated tool of image analysis. Clinical and outcome data of the cilengitide-treated patients were similar to those of the EORTC/NCIC trial except for a higher proportion of patients with a methylated O(6)-methylguanyl-DNA-methyltransferase gene promoter. Analysis of recurrence pattern revealed neither a difference in the size of the recurrent tumor nor in the distance of the recurrences from the preoperative tumor location between groups. Overall frequencies of distant recurrences were 20 % in the reference group and 19 % (4/21 patients) in the cilengitide group. Compared with TMZ/RT â TMZ alone, the addition of cilengitide does not alter patterns of progression. This analysis does not support concerns that integrin antagonism by cilengitide may induce a more aggressive phenotype at progression, but also provides no evidence for an anti-invasive activity of cilengitide in patients with newly diagnosed glioblastoma.
Assuntos
Inibidores da Angiogênese/administração & dosagem , Neoplasias Encefálicas/tratamento farmacológico , Glioblastoma/tratamento farmacológico , Venenos de Serpentes/administração & dosagem , Adulto , Idoso , Antineoplásicos Alquilantes/administração & dosagem , Neoplasias Encefálicas/patologia , Neoplasias Encefálicas/terapia , Quimiorradioterapia , Quimioterapia Adjuvante , Dacarbazina/administração & dosagem , Dacarbazina/análogos & derivados , Progressão da Doença , Feminino , Glioblastoma/patologia , Glioblastoma/terapia , Humanos , Processamento de Imagem Assistida por Computador , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/tratamento farmacológico , Recidiva Local de Neoplasia/patologia , Temozolomida , Resultado do TratamentoRESUMO
BACKGROUND: Treatment of recurrent anaplastic glioma and glioblastoma remains a particular challenge in neurooncology. The lack of controlled trials results in poor evidence for all therapeutic options. Upon recurrence, many patients are treated with bevacizumab or one of the frequently used nitrosoureas such as lomustine. However, patients who still present in overall good condition after failure of multiple lines of therapy may ask for additional therapy. METHODS: Here, we report our experience with the use of carboplatin in combination with etoposide as fourth- or fifth-line therapy in patients with progressive high-grade glioma. RESULTS: The median Karnofsky performance status at the beginning of treatment was 80%. The median progression-free survival (PFS) was 2.5 months. PFS at 6 months was 0%. Administration of carboplatin and etoposide was associated with grade 3 or 4 hematotoxicity in 8 of 12 patients. CONCLUSION: Carboplatin in combination with etoposide has an unfavorable risk-benefit profile in heavily pretreated glioma patients.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Neoplasias Encefálicas/tratamento farmacológico , Carboplatina/administração & dosagem , Progressão da Doença , Etoposídeo/administração & dosagem , Glioma/tratamento farmacológico , Adulto , Idoso , Neoplasias Encefálicas/diagnóstico , Feminino , Glioma/diagnóstico , Humanos , Masculino , Pessoa de Meia-Idade , Estudos RetrospectivosRESUMO
The prognosis of patients afflicted by glioblastoma remains poor. Biomarkers for the disease would be desirable in order to allow for an early detection of tumor progression or to indicate rapidly growing tumor subtypes requiring more intensive therapy. In this study, we investigated whether a blood-derived specific miRNA fingerprint can be defined in patients with glioblastoma. To this end, miRNA profiles from the blood of 20 patients with glioblastoma and 20 age- and sex-matched healthy controls were compared. Of 1158 tested miRNAs, 52 were significantly deregulated, as assessed by unadjusted Student's t-test at an alpha level of 0.05. Of these, two candidates, miR-128 (up-regulated) and miR-342-3p (down-regulated), remained significant after correcting for multiple testing by Benjamini-Hochberg adjustment with a p-value of 0.025. The altered expression of these two biomarkers was confirmed in a second cohort of glioblastoma patients and healthy controls by real-time PCR and validated for patients who had received neither radio- nor chemotherapy and for patients who had their glioblastomas resected more than 6 months ago. Moreover, using machine learning, a comprehensive miRNA signature was obtained that allowed for the discrimination between blood samples of glioblastoma patients and healthy controls with an accuracy of 81% [95% confidence interval (CI) 78-84%], specificity of 79% (95% CI 75-83%) and sensitivity of 83% (95% CI 71-85%). In summary, our proof-of-concept study demonstrates that blood-derived glioblastoma-associated characteristic miRNA fingerprints may be suitable biomarkers and warrant further exploration.
Assuntos
Biomarcadores Tumorais/sangue , Neoplasias Encefálicas/sangue , Glioblastoma/sangue , MicroRNAs/sangue , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias Encefálicas/patologia , Interpretação Estatística de Dados , Progressão da Doença , Feminino , Glioblastoma/patologia , Humanos , Masculino , Análise em Microsséries , Pessoa de Meia-Idade , Reação em Cadeia da Polimerase Via Transcriptase ReversaAssuntos
Anticorpos Monoclonais Humanizados/administração & dosagem , Antineoplásicos/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Encefálicas/tratamento farmacológico , Glioblastoma/tratamento farmacológico , Lomustina/administração & dosagem , Recidiva Local de Neoplasia/tratamento farmacológico , Adulto , Idoso , Antineoplásicos/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Bevacizumab , Progressão da Doença , Feminino , Humanos , Lomustina/efeitos adversos , Masculino , Pessoa de Meia-Idade , Estudos RetrospectivosRESUMO
BACKGROUND: During the course of disease, most glioma patients learn that there is no cure for their tumor. It is therefore not uncommon for patients or caregivers to seek complementary and alternative medicine (CAM) treatments. Patterns of CAM use vary across the globe, but little is known about the type of, and motivation for, CAM use in most countries. METHODS: Here we conducted a cross-sectional survey of CAM use in patients harboring gliomas of World Health Organization (WHO) grades II to IV at 3 specialized neuro-oncology centers in Switzerland. RESULTS: Of 208 patients who returned the survey, approximately half reported having used or using CAM. CAM use was associated with younger age. Patients suffering from WHO grade II gliomas were less likely to indicate CAM use. The leading motivation for CAM use was to contribute actively to the treatment of the disease. CAM use was commonly not counseled or supervised by a health care professional. Cost and issues of reimbursement were not an important factor in the decision against or for CAM use. CONCLUSIONS: Physicians caring for glioma patients should be aware of and explore CAM use to better understand patients' attitudes toward their disease, to provide counseling, and to identify potential interactions of CAM with standard treatments for gliomas.
RESUMO
Subpial hemorrhage is a rare finding in patients with a variable spectrum of neurological symptoms and signs. Here we present a series of 10 patients with subpial hemorrhage, 53 to 80 years old, diagnosed and treated within the last 4 years at a single center. Patients were identified based on imaging criteria with either magnetic resonance imaging (MRI) or computed tomography (CT) showing blood along the cortical surface. Presenting symptoms were diverse, with seizures being the most frequent followed by headaches and focal neurological signs such as sensory or motor deficits. Of 7 patients undergoing lumbar puncture, none showed fresh blood or cerebrospinal fluid (CSF) xanthochromia. Neither digital subtraction angiography (DSA) nor MR venography (MRV) confirmed cerebral vein thrombosis as a possible etiologic factor for subpial hemorrhage. Patients for whom follow-up was available (n=8), showed complete recovery indicating an excellent prognosis. Overall, the etiology of subpial hemorrhage remains obscure. Treatment should be symptomatic with particular attention to antiepileptic medication.
Assuntos
Hematoma Subdural/complicações , Hematoma Subdural/diagnóstico , Hematoma Subdural/terapia , Doenças do Sistema Nervoso , Idoso , Idoso de 80 Anos ou mais , Feminino , Seguimentos , Hematoma Subdural/líquido cefalorraquidiano , Humanos , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Doenças do Sistema Nervoso/diagnóstico , Doenças do Sistema Nervoso/etiologia , Doenças do Sistema Nervoso/terapia , Exame Neurológico/métodos , Tomografia Computadorizada por Raios XRESUMO
NKG2D ligands (NKG2DL) are expressed by infected and transformed cells. They transmit danger signals to NKG2D-expressing immune cells, leading to lysis of NKG2DL-expressing cells. We here report that the NKG2DL MHC class I-chain-related molecules A and B (MICA/B) and UL16-binding proteins (ULBP) 1-3 are expressed in human brain tumours in vivo, while expression levels are low or undetectable in normal brain. MICA and ULBP2 expression decrease with increasing WHO grade of malignancy, while MICB and ULBP1 are expressed independently of tumour grade. We further delineate two independent mechanisms that can explain these expression patterns: (i) transforming growth factor-beta (TGF-beta) is upregulated during malignant progression and selectively downregulates MICA, ULBP2 and ULBP4 expression, while MICB, ULBP1 and ULBP3 are unaffected. (ii) Cleavage of MICA and ULBP2 is reduced by inhibition of metalloproteinases (MP), whereas no changes in the expression levels of other NKG2DL were detected. Consequently, NKG2DL-dependent NK cell-mediated lysis is enhanced by depletion of TGF-beta or inhibition of MP. Thus, escape from NKG2D-mediated immune surveillance of malignant gliomas in vivo may be promoted by the inhibition of MICA and ULBP2 expression via an autocrine TGF-beta loop and by MP-dependent shedding from the cell surface. Loss of MICA and ULBP2, in contrast to other NKG2DL, may be particularly important in glioma immune escape, and differential regulation of human NKG2DL expression is part of the immunosuppressive properties of human malignant glioma cells.
Assuntos
Neoplasias Encefálicas/imunologia , Glioma/imunologia , Antígenos de Histocompatibilidade Classe I/imunologia , Metaloproteases/imunologia , Receptores Imunológicos/imunologia , Fator de Crescimento Transformador beta/imunologia , Neoplasias Encefálicas/química , Neoplasias Encefálicas/metabolismo , Proteínas de Transporte/análise , Proteínas de Transporte/imunologia , Morte Celular/imunologia , Linhagem Celular Tumoral , Regulação para Baixo/imunologia , Proteínas Ligadas por GPI , Glioma/química , Glioma/metabolismo , Antígenos de Histocompatibilidade Classe I/análise , Humanos , Imuno-Histoquímica/métodos , Peptídeos e Proteínas de Sinalização Intercelular , Peptídeos e Proteínas de Sinalização Intracelular , Células Matadoras Naturais/imunologia , Proteínas de Membrana/análise , Proteínas de Membrana/imunologia , Metaloproteases/metabolismo , Subfamília K de Receptores Semelhantes a Lectina de Células NK , Receptores Imunológicos/análise , Receptores de Células Matadoras Naturais , Fator de Crescimento Transformador beta/metabolismo , Regulação para Cima/imunologiaRESUMO
Transforming growth factor (TGF)-beta is the key molecule implicated in impaired immune function in human patients with malignant gliomas. Here we report that patients with glioblastoma, the most common and lethal type of human glioma, show decreased expression of the activating immunoreceptor NKG2D in CD8(+) T and natural killer (NK) cells. TGF-beta is responsible for the down-regulation of NKG2D expression in CD8(+) T and NK cells mediated by serum and cerebrospinal fluid of glioma patients in vitro. Moreover, TGF-beta inhibits the transcription of the NKG2D ligand MICA. Interference with the synthesis of TGF-beta1 and TGF-beta2 by small interfering RNA technology prevents the down-regulation of NKG2D on immune cells mediated by LNT-229 glioma cell supernatant and strongly enhances MICA expression in the glioma cells and promotes their recognition and lysis by CD8(+) T and NK cells. Furthermore, TGF-beta silencing results in a less migratory and invasive glioma cell phenotype in vitro. LNT-229 glioma cells deficient in TGF-beta exhibit a loss of subcutaneous and orthotopic tumorigenicity in nude mice, and NK cells isolated from these mice show an activated phenotype. RNA interference targeting TGF-beta1,2 results in a glioma cell phenotype that is more sensitive to immune cell lysis and less motile in vitro and nontumorigenic in nude mice, strongly confirming TGF-beta antagonism as a major therapeutic strategy for the future treatment of malignant gliomas.
Assuntos
Movimento Celular/imunologia , Glioblastoma/imunologia , Interferência de RNA/imunologia , Receptores Imunológicos/imunologia , Fator de Crescimento Transformador beta/imunologia , Idoso , Regulação para Baixo , Feminino , Regulação Neoplásica da Expressão Gênica , Inativação Gênica , Glioblastoma/genética , Glioblastoma/patologia , Humanos , Células Matadoras Naturais/imunologia , Masculino , Pessoa de Meia-Idade , Subfamília K de Receptores Semelhantes a Lectina de Células NK , Invasividade Neoplásica , Receptores Imunológicos/biossíntese , Receptores Imunológicos/genética , Receptores de Células Matadoras Naturais , Transfecção , Fator de Crescimento Transformador beta/genéticaRESUMO
Immunotherapy targeting glioblastoma initiating cells (GIC) is considered a promising strategy. However, GIC are prone to evade immune response and there is a need for potent adjuvants. IFN-ß might enhance the immune response and here we define its net effect on the innate immunogenicity of GIC. The transcriptomes of GIC treated with IFN-ß and controls were assessed by microarray-based expression profiling for altered expression of immune regulatory genes. Several genes involved in adaptive and innate immune responses were regulated by IFN-ß. We validated these results using reverse transcription (RT)-PCR and flow cytometry for corresponding protein levels. The up-regulation of the NK cell inhibitory molecules HLA-E and MHC class I was balanced by immune stimulating effects including the up-regulation of nectin-2. In 3 out of 5 GIC lines tested we found a net immune stimulating effect of IFN-ß in cytotoxicity assays using NKL cells as effectors. IFN-ß therefore warrants further investigation as an adjuvant for immunotherapy targeting GIC.
Assuntos
Glioblastoma/imunologia , Imunidade Inata/efeitos dos fármacos , Interferon beta/farmacologia , Moléculas de Adesão Celular/genética , Linhagem Celular Tumoral , Genes MHC Classe I/genética , Glioblastoma/genética , Antígenos de Histocompatibilidade Classe I/genética , Humanos , Nectinas , Regulação para Cima/efeitos dos fármacosRESUMO
OPINION STATEMENT: Primary central nervous system lymphoma is a particular challenge in clinical neuro-oncology. In contrast to most other malignant brain tumors, it may be considered a curable disease at least in younger patients who can tolerate intensive treatment regimens. Yet, therapeutic progress has been limited with little measurable improvement in outcome over the last two decades, mainly due to the low incidence of this tumor, which impedes the execution of large randomized clinical trials, and the failure of most large cooperative groups to conduct such trials. Whenever possible, high-dose methotrexate (HD-MTX) is the backbone of the therapeutic regimen. Response rates can be increased by the addition of second agents like ifosfamide or cytarabine, however, their impact on overall survival is less clear. Similarly, the use of the anti-CD20 antibody rituximab, commonly used in the treatment of B cell lymphomas outside the CNS, remains controversial and has not been examined in adequate clinical trials. The prognosis of patients, who do not qualify for HD-MTX-based chemotherapy, is considerably poorer. Radiation therapy is an active treatment with high response rates but does typically not result in long-lasting remissions. It remains an important therapeutic option as a salvage therapy in patients progressing on or no longer responding to HD-MTX-based treatment. The combination of HD-MTX and radiation therapy does not prolong overall survival. It is associated with significant neurotoxicity, and it should be avoided. Another matter of debate is whether consolidation therapy by other means, such as high-dose chemotherapy followed by stem cell support, is the most promising regimen. Given these numerous uncertainties, neuro-oncologists should strive for a treatment of PCNSL patients within clinical trials to allow for the development of improved therapeutic regimens.
RESUMO
BACKGROUND: There are emerging reports that the family of a disintegrin and metalloproteinases (ADAM) are involved in the maintenance of the malignant phenotype of glioblastomas. Notably, ADAM proteases 10 and 17 might impair the immune recognition of glioma cells via the activating immunoreceptor NKG2D by cleavage of its ligands from the cell surface. Glioblastoma-initiating cells (GIC) with stem cell properties have been identified as an attractive target for immunotherapy. However, GIC immunogenicity seems to be low. METHODS AND RESULTS: Here,we show that ADAM10 and ADAM17 are expressed on the cell surface of GIC and contribute to an immunosuppressive phenotype by cleavage of ULBP2. The cell surface expression of ULBP2 is enhanced upon blocking ADAM10 and ADAM17, and treatment with ADAM10 and ADAM17specific inhibitors leads to enhanced immunerecognition of GIC by natural killer cells. CONCLUSIONS: Therefore, ADAM10 and ADAM17 constitute suitable targets to boost an immune response against GIC.
Assuntos
Proteínas ADAM/metabolismo , Secretases da Proteína Precursora do Amiloide/metabolismo , Neoplasias Encefálicas/imunologia , Glioblastoma/imunologia , Proteínas de Membrana/metabolismo , Células-Tronco Neoplásicas/imunologia , Proteínas ADAM/antagonistas & inibidores , Proteína ADAM10 , Proteína ADAM17 , Secretases da Proteína Precursora do Amiloide/antagonistas & inibidores , Linhagem Celular Tumoral , Sobrevivência Celular , Dipeptídeos/farmacologia , Proteínas Ligadas por GPI/metabolismo , Humanos , Ácidos Hidroxâmicos/farmacologia , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Proteínas de Membrana/antagonistas & inibidores , Subfamília K de Receptores Semelhantes a Lectina de Células NK/metabolismo , Receptores de Fatores de Crescimento Transformadores beta/antagonistas & inibidoresRESUMO
The treatment of glioblastoma remains a major challenge for clinicians since these highly aggressive brain tumors are relatively resistant towards radio- and chemotherapy. The pathways that control apoptosis are altered in glioblastoma cells leading to resistance towards apoptotic stimuli in general. In this review we describe the alterations affecting the p53 pathway, the BCL-2 protein family, the inhibitor of apoptosis proteins and several growth factor pathways involved in the regulation of programmed cell death and define possible targets for new therapies within these apoptotic pathways in glioblastomas. Moreover, we review strategies to target death receptor pathways, most notably to render the glioblastoma cells more susceptible towards this approach without enhancing toxicity in general. Most of the strategies targeting apoptosis in glioblastomas presented here are in a pre-clinical stage of development, however, they all share the ultimative goal to improve the outcome for glioblastoma patients.
Assuntos
Apoptose , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/patologia , Glioblastoma/tratamento farmacológico , Glioblastoma/patologia , Animais , Morte Celular , Proteína Ligante Fas/metabolismo , Regulação Neoplásica da Expressão Gênica , Genes p53 , Humanos , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Camundongos , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Proteína Supressora de Tumor p53/metabolismoRESUMO
The treatment of glioblastoma remains a major challenge in the field of neuro-oncology. There is emerging evidence that glioblastomas consist of heterogeneous cell populations with a small subset of cells with stem cell-like properties which might be resistant to conventional therapy and are thus crucial for tumor recurrence. These glioma-initiating cells (GICs) are therefore an attractive therapeutic target. Death receptor activation is one promising approach of cancer therapy. The synthetic hexameric cluster of differentiation 95 (CD95) agonist APO010 exhibits strong antiglioma activity towards human glioma cell lines, as well as in cell cultures of primary glioblastoma. Here, we investigated the ability of APO010 to induce cell death in a panel of previously well-defined GIC lines. The GIC lines and their derived differentiated cultures expressed CD95 on the cell surface and were sensitive towards APO010-mediated cell death to a variable extent. Temozolomide enhanced sensitivity of GICs to APO010. APO010 warrants being further evaluated as a tool to target GICs.
Assuntos
Apoptose/efeitos dos fármacos , Proteína Ligante Fas/metabolismo , Glioblastoma/patologia , Células-Tronco Neoplásicas/patologia , Proteínas Recombinantes de Fusão/farmacologia , Antígeno AC133 , Antígenos CD/imunologia , Antineoplásicos Alquilantes/farmacologia , Linhagem Celular Tumoral , Dacarbazina/análogos & derivados , Dacarbazina/farmacologia , Glioblastoma/imunologia , Glicoproteínas/imunologia , Humanos , Células-Tronco Neoplásicas/imunologia , Peptídeos/imunologia , TemozolomidaRESUMO
Brain tumors of different origin, but notably malignant gliomas, are characterized by their immunosuppressive properties which allow them to escape the host's immune surveillance. The activating immune cell ligands that are expressed by tumor cells, together with potentially immunogenic antigens, are overridden by numerous immune inhibitory signals, with TGF-3 as the master immunosuppressive molecule (Figure 4.1).The ongoing investigation of mechanisms of tumor-derived immunosuppression allows for an increasing understanding of brain tumor immunology. Targeting different mechanisms of tumor-derived immunosuppression, such as inhibition of TGF-[, may represent a promising strategy for future immunotherapeutic approaches.
Assuntos
Alergia e Imunologia , Antígenos de Neoplasias , Neoplasias Encefálicas/imunologia , Fenômenos do Sistema Imunitário/fisiologia , Neoplasias Encefálicas/patologia , HumanosRESUMO
Cancer stem cells are an attractive target for immunotherapeutic approaches to glioblastoma. However, an immune inhibitory phenotype of cells currently classified as "glioma-initiating cells" (GIC) might counteract recognition by immune effector cells. Here, we investigate the contribution of the non-classical MHC molecule HLA-E to the immunosuppressive phenotype of GIC. HLA-E is expressed in GIC lines and its expression is reduced upon differentiation of GIC in serum-containing culture conditions. Constitutive HLA-E inhibits natural killer (NK) cell-mediated lysis of GIC since small-interfering RNA-mediated HLA-E gene silencing enhances the immunogenicity of GIC. Increased GIC lysis was observed both in the CD133+ and in the CD133- compartment. Furthermore, the use of interferon-γ as a possible agent to boost an immune response against glioblastoma cells might be limited by the concurrent upregulation of HLA-E.
Assuntos
Neoplasias Encefálicas/imunologia , Glioblastoma/imunologia , Antígenos de Histocompatibilidade Classe I/imunologia , Células-Tronco Neoplásicas/imunologia , Linhagem Celular Tumoral , Citometria de Fluxo , Humanos , Células Matadoras Naturais/imunologia , Células-Tronco Neoplásicas/citologia , Fenótipo , Reação em Cadeia da Polimerase em Tempo Real , Antígenos HLA-ERESUMO
Death receptor targeting has emerged as one of the promising novel approaches of cancer therapy. The activation of one such prototypic death receptor, CD95 (Fas/APO-1), has remained controversial because CD95 agonistic molecules have exhibited either too strong toxicity or too little activity. The natural CD95 ligand (CD95L) is a cytokine, which needs to trimerize to mediate a cell death signal. Mega-Fas-Ligand, now referred to as APO010, is a synthetic hexameric CD95 agonist that exhibits strong antitumor activity in various tumor models. Here, we studied the effects of APO010 in human glioma models in vitro and in vivo. Compared with a cross-linked soluble CD95L or a CD95-agonistic antibody, APO010 exhibited superior activity in glioma cell lines expressing CD95 and triggered caspase-dependent cell death. APO010 reduced glioma cell viability in synergy when combined with temozolomide. The locoregional administration of APO010 induced glioma cell death in vivo and prolonged the survival of tumor-bearing mice. A further exploration of APO010 as a novel antiglioma agent is warranted.