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1.
BMC Neurol ; 23(1): 9, 2023 Jan 07.
Artigo em Inglês | MEDLINE | ID: mdl-36609238

RESUMO

BACKGROUND: Glioblastoma (GBM) infrequently recurs in the infratentorial region. Such Infratentorial recurrence (ITR) has some clinically unique characteristics, such as presenting unspecific symptoms and providing patients a chance to receive additional radiotherapy. However, the clinical significances of ITR are not well studied. METHODS: We reviewed newly diagnosed isocitrate dehydrogenase (IDH)-wildtype GBM patients treated at our institution between October 2008 and December 2018. ITR was defined as any type of recurrence in GBM, including dissemination or distant recurrence, which primarily developed in the supratentorial region and recurred in the infratentorial region. RESULTS: Of 134 patients with newly diagnosed IDH-wildtype GBM, six (4.5%) were classified as having ITR. There was no significant difference in median duration from the first surgery to ITR development between patients with and without ITR (12.2 vs. 10.2 months, P = 0.65). The primary symptoms of ITR were gait disturbance (100%, n = 6), dizziness (50.0%, n = 3), nausea (33.3%, n = 2), and cerebellar mutism (16.7%, n = 1). In four cases (66.7%), symptoms were presented before ITR development. All patients received additional treatments for ITR. The median post-recurrence survival (PRS) of ITR patients was significantly shorter than that of general GBM patients (5.5 vs. 9.1 months, P = 0.023). However, chemoradiotherapy contributed to palliating symptoms such as nausea. CONCLUSIONS: ITR is a severe recurrence type in GBM patients. Its symptoms are neurologically unspecific and can be overlooked or misdiagnosed as side effects of treatments. Carefully checking the infratentorial region, especially around the fourth ventricle, is essential during the GBM patient follow-up.


Assuntos
Neoplasias Encefálicas , Glioblastoma , Humanos , Glioblastoma/terapia , Neoplasias Encefálicas/diagnóstico , Prognóstico , Estudos Retrospectivos
2.
Sci Transl Med ; 15(677): eabo4778, 2023 Jan 04.
Artigo em Inglês | MEDLINE | ID: mdl-36599004

RESUMO

The administration of inactivated tumor cells is known to induce a potent antitumor immune response; however, the efficacy of such an approach is limited by its inability to kill tumor cells before inducing the immune responses. Unlike inactivated tumor cells, living tumor cells have the ability to track and target tumors. Here, we developed a bifunctional whole cancer cell-based therapeutic with direct tumor killing and immunostimulatory roles. We repurposed the tumor cells from interferon-ß (IFN-ß) sensitive to resistant using CRISPR-Cas9 by knocking out the IFN-ß-specific receptor and subsequently engineered them to release immunomodulatory agents IFN-ß and granulocyte-macrophage colony-stimulating factor. These engineered therapeutic tumor cells (ThTCs) eliminated established glioblastoma tumors in mice by inducing caspase-mediated cancer cell apoptosis, down-regulating cancer-associated fibroblast-expressed platelet-derived growth factor receptor ß, and activating antitumor immune cell trafficking and antigen-specific T cell activation signaling. This mechanism-based efficacy of ThTCs translated into a survival benefit and long-term immunity in primary, recurrent, and metastatic cancer models in immunocompetent and humanized mice. The incorporation of a double kill-switch comprising herpes simplex virus-1 thymidine kinase and rapamycin-activated caspase 9 in ThTCs ensured the safety of our approach. Arming naturally neoantigen-rich tumor cells with bifunctional therapeutics represents a promising cell-based immunotherapy for solid tumors and establishes a road map toward clinical translation.


Assuntos
Vacinas Anticâncer , Glioblastoma , Herpesvirus Humano 1 , Animais , Camundongos , Imunoterapia , Imunização , Glioblastoma/terapia
3.
Sci Rep ; 13(1): 196, 2023 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-36604465

RESUMO

Naïve T cells become effector T cells following stimulation by antigen-loaded dendritic cells (DCs) and sequential cytokine activation. We aimed to develop procedures to efficiently activate T cells with tumor-associated antigens (TAAs) to glioblastoma (GBM) stem cells. To remove antigen presentation outside of the immunosuppressive tumor milieu, three different glioma stem cell (GSC) specific antigen sources to load DCs were compared in their ability to stimulate lymphocytes. An activated T cell (ATC) protocol including cytokine activation and expansion in culture to target GSCs was generated and optimized for a planned phase I clinical trial. We compared three different antigen-loading methods on DCs to effectively activate T cells, which were GBM patient-derived GSC-lysate, acid-eluate of GSCs and synthetic peptides derived from proteins expressed in GSCs. DCs derived from HLA-A2 positive blood sample were loaded with TAAs. Autologous T cells were activated by co-culturing with loaded DCs. Efficiency and cytotoxicity of ATCs were evaluated by targeting TAA-pulsed DCs or T2 cells, GSCs, or autologous PHA-blasts. Characteristics of ATCs were evaluated by Flow Cytometry and ELISpot assay, which showed increased number of ATCs secreting IFN-γ targeting GSCs as compared with non-activated T cells and unloaded target cells. Neither GSC-lysate nor acid-eluate loading showed enhancement in response of ATCs but the synthetic peptide pool showed significantly increased IFN-γ secretion and increased cytotoxicity towards target cells. These results demonstrate that ATCs activated using a TAA synthetic peptide pool efficiently enhance cytotoxicity specifically to target cells including GSC.


Assuntos
Glioblastoma , Linfócitos T Citotóxicos , Humanos , Glioblastoma/terapia , Glioblastoma/metabolismo , Interferon gama/metabolismo , Antígenos de Neoplasias , Peptídeos/metabolismo , Células-Tronco Neoplásicas/metabolismo , Terapia Baseada em Transplante de Células e Tecidos , Células Dendríticas
4.
Gen Physiol Biophys ; 42(1): 97-106, 2023 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-36705309

RESUMO

The low-frequency pulsed electromagnetic field (PEMF) may have possible cytoprotective effects against the destructive effects of oxidative stress. The goal was to investigate if shortterm low-frequency PEMF has cytoprotective effects in glioblastoma cell line following high-dose hydrogen peroxide (H2O2) treatment. U87-MG cells were divided into four groups: Sham-control group; PEMF group (cells exposed to PEMF); H2O2 group (cells treated with H2O2 at time intervals 30 min and 48 h, respectively); H2O2+PEMF group (cells exposed to PEMF after H2O2 treatment at time intervals 30 min and 48 h, respectively). The cell viability, levels of reactive oxygen species, glutathione peroxidase activity, and the amount of glutathione were measured. The cytoprotective effect of PEMF against deleterious effects of oxidative stress triggered by different time interval of H2O2 treatment might be mediated by the increase in the cell viability, the elevation in the antioxidant enzyme activity/amount, and the decrease in the reactive oxygen species level. In addition, the cytoprotective effect of PEMF varies depending on different time intervals of H2O2 treatment. In the light of these findings, further in vivo and/or in vitro studies on neurophysiological effects of PEMFs and their underlying molecular mechanisms are needed to elucidate neurotoxic or neuroprotective role against antioxidant defense mechanisms.


Assuntos
Campos Eletromagnéticos , Glioblastoma , Humanos , Espécies Reativas de Oxigênio/metabolismo , Antioxidantes/farmacologia , Peróxido de Hidrogênio/farmacologia , Glioblastoma/terapia , Estresse Oxidativo
5.
J Neurooncol ; 161(1): 147-153, 2023 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-36609807

RESUMO

PURPOSE: In the randomized phase III trial CeTeG/NOA-09, temozolomide (TMZ)/lomustine (CCNU) combination therapy was superior to TMZ in newly diagnosed MGMT methylated glioblastoma, albeit reporting more frequent hematotoxicity. Here, we analyze high grade hematotoxicity and its prognostic relevance in the trial population. METHODS: Descriptive and comparative analysis of hematotoxicity adverse events ≥ grade 3 (HAE) according to the Common Terminology of Clinical Adverse Events, version 4.0 was performed. The association of HAE with survival was assessed in a landmark analysis. Logistic regression analysis was performed to predict HAE during the concomitant phase of chemotherapy. RESULTS: HAE occurred in 36.4% and 28.6% of patients under CCNU/TMZ and TMZ treatment, respectively. The median onset of the first HAE was during concomitant chemotherapy (i.e. first CCNU/TMZ course or daily TMZ therapy), and 42.9% of patients with HAE receiving further courses experienced repeat HAE. Median HAE duration was similar between treatment arms (CCNU/TMZ 11.5; TMZ 13 days). Chemotherapy was more often discontinued due to HAE in CCNU/TMZ than in TMZ (19.7 vs. 6.3%, p = 0.036). The occurrence of HAE was not associated with survival differences (p = 0.76). Regression analysis confirmed older age (OR 1.08) and female sex (OR 2.47), but not treatment arm, as predictors of HAE. CONCLUSION: Older age and female sex are associated with higher incidence of HAE. Although occurrence of HAE was not associated with shorter survival, reliable prediction of patients at risk might be beneficial to allow optimal management of therapy and allocation of supportive measures. TRIAL REGISTRATION: NCT01149109.


Assuntos
Neoplasias Encefálicas , Glioblastoma , Humanos , Feminino , Temozolomida/uso terapêutico , Lomustina/uso terapêutico , Prognóstico , Dacarbazina/efeitos adversos , Neoplasias Encefálicas/terapia , Glioblastoma/terapia , Antineoplásicos Alquilantes/efeitos adversos
6.
Tidsskr Nor Laegeforen ; 143(2)2023 Jan 31.
Artigo em Norueguês | MEDLINE | ID: mdl-36718891

RESUMO

Glioblastoma is the most common form of primary brain cancer in adults, and the disease has a serious prognosis. Although great progress has been made in molecular characteristics, no major breakthroughs in treatment have been achieved for many years. In this article we present a clinical review of current diagnostics and treatment, as well as the challenges and opportunities inherent in developing improved and more personalised treatment.


Assuntos
Neoplasias Encefálicas , Glioblastoma , Humanos , Adulto , Glioblastoma/diagnóstico , Glioblastoma/terapia , Prognóstico , Neoplasias Encefálicas/diagnóstico por imagem , Neoplasias Encefálicas/terapia
7.
J Clin Invest ; 133(1)2023 01 03.
Artigo em Inglês | MEDLINE | ID: mdl-36594465

RESUMO

Glioblastoma (GBM) is the most belligerent and frequent brain tumor in adults. Research over the past two decades has provided increased knowledge of the genomic and molecular landscape of GBM and highlighted the presence of a high degree of inter- and intratumor heterogeneity within the neoplastic compartment. It is now appreciated that GBMs are composed of multiple distinct and impressionable neoplastic and non-neoplastic cell types that form the unique brain tumor microenvironment (TME). Non-neoplastic cells in the TME form reciprocal interactions with neoplastic cells to promote tumor growth and invasion, and together they influence the tumor response to standard-of-care therapies as well as emerging immunotherapies. One of the most prevalent non-neoplastic cell types in the GBM TME are myeloid cells, the most abundant of which are of hematopoietic origin, including monocytes/monocyte-derived macrophages. Less abundant, although still a notable presence, are neutrophils of hematopoietic origin and intrinsic brain-resident microglia. In this Review we focus on neutrophils and monocytes that infiltrate tumors from the blood circulation, their heterogeneity, and their interactions with neoplastic cells and other non-neoplastic cells in the TME. We conclude with an overview of challenges in targeting these cells and discuss avenues for therapeutic exploitation to improve the dismal outcomes of patients with GBM.


Assuntos
Neoplasias Encefálicas , Glioblastoma , Humanos , Monócitos/patologia , Glioblastoma/genética , Glioblastoma/terapia , Glioblastoma/metabolismo , Neutrófilos/patologia , Macrófagos/metabolismo , Microglia/patologia , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/terapia , Neoplasias Encefálicas/metabolismo , Microambiente Tumoral/genética
8.
ACS Appl Mater Interfaces ; 15(1): 67-76, 2023 Jan 11.
Artigo em Inglês | MEDLINE | ID: mdl-36508395

RESUMO

Glioblastoma is the most common type of primary brain tumor, which has a high recurrence rate and a high mortality rate. Immunotherapy shows promise in cancer therapy due to its capacity to manipulate the immune system to attack tumor cells with less toxic and durable immune responses. However, the low immunogenicity and limited immune cell infiltration in a glioblastoma lead to a weakened antitumor immune response, resulting in suboptimal therapeutic efficacy. A compelling solution is provided by oncolytic adenovirus (OAs), which can selectively replicate within tumor cells while simultaneously promoting antitumor immunity. Herein, we constructed an oncolytic adenovirus reservoir (OAR) by shocking OA-loaded tumor cells in liquid nitrogen to eliminate proliferation and pathogenicity. OARs showed sustained OAs release and effectively lysed tumor cells in vitro and in vivo. In a mouse intracranial glioblastoma model, OARs could efficiently induce dendritic cells' maturation, facilitate the tumor recruitment, and promote the infiltration of cytotoxic effector T lymphocytes via a single treatment, resulting in specific antitumor immune responses and long-term animal survival. Taken together, these results demonstrated that OAR is a promising synergistic therapeutic strategy for treating glioblastoma.


Assuntos
Adenoviridae , Glioblastoma , Camundongos , Animais , Adenoviridae/genética , Linhagem Celular Tumoral , Glioblastoma/terapia , Imunoterapia/métodos , Linfócitos T Citotóxicos
9.
Biomaterials ; 293: 121981, 2023 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-36580721

RESUMO

Glioblastoma stem cells (GSCs) are subpopulations of tumor-initiating cells responsible for glioblastoma (GBM) tumorigenesis and recurrence. Dual inhibition of vascular endothelium and GSCs is still a challenge due to their different pathological features. Here we present a combined all-in-control strategy to realize a local photothermal therapy (PTT). We designed T-cell-mimic nanoparticles with aggregation-induced emission (AIE) characteristics by coating the genetically engineered T cell membrane (CM) onto AIE nanoparticles (CM@AIE NPs). The CM shell was designed against CD133 and epidermal growth factor receptor (EGFR) which provides the possibility to target both GBM cells and GSCs for cancer therapy. CM@AIE NPs can serve as the tight junction (TJ) modulators to trigger an intracellular signaling cascade, causing TJ disruption and actin cytoskeleton reorganization to allow CM@AIE NPs to cross the blood-brain barrier (BBB) silently. The 980 nm excitation-triggered PTT can completely inhibit tumorigenesis and recurrence. The combination of CM-coating nanotechnology and genetic editing technique can inspire further development of synergetic techniques for preventing GBM recurrence.


Assuntos
Neoplasias Encefálicas , Glioblastoma , Nanopartículas , Humanos , Glioblastoma/genética , Glioblastoma/terapia , Glioblastoma/metabolismo , Linfócitos T/metabolismo , Membrana Celular/metabolismo , Carcinogênese/patologia , Neoplasias Encefálicas/prevenção & controle , Neoplasias Encefálicas/metabolismo , Linhagem Celular Tumoral , Células-Tronco Neoplásicas/patologia
10.
Eur J Cancer ; 179: 113-120, 2023 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-36521332

RESUMO

During the V Siena Immuno-Oncology (IO) Think Tank meeting in 2021, conditions were discussed which favor immunotherapy responses in either primary or secondary brain malignancies. Core elements of these discussions have been reinforced by important publications in 2021 and 2022. In primary brain tumors (such as glioblastoma) current immunotherapies have failed to deliver meaningful clinical benefit. By contrast, brain metastases frequently respond to current immunotherapies. The main differences between both conditions seem to be related to intrinsic factors (e.g., type of driver mutations) and more importantly extrinsic factors, such as the blood brain barrier and immune suppressive microenvironment (e.g., T cell counts, functional differences in T cells, myeloid cells). Future therapeutic interventions may therefore focus on rebalancing the immune cell population in a way which enables the host to respond to current or future immunotherapies.


Assuntos
Neoplasias Encefálicas , Glioblastoma , Humanos , Neoplasias Encefálicas/terapia , Imunoterapia , Glioblastoma/terapia , Oncologia , Microambiente Tumoral
11.
Medicine (Baltimore) ; 101(47): e32042, 2022 Nov 25.
Artigo em Inglês | MEDLINE | ID: mdl-36451503

RESUMO

BACKGROUND: To fully understand the clinical features and prognosis of Glioblastoma (GBM), we extracted the data from the Surveillance, Epidemiology, and End Results (SEER) database and performed a series of analyses. METHODS: We retrospectively analyzed the data of 1674 patients with GBM obtained from the SEER database from 1983 to 2015. Kaplan-Meier analysis was performed to calculate the survival rate, and the log-rank test was used to analyze the survival outcomes. RESULTS: Older patients with GBM had a worse survival period (P < .05). Laterality had no effect on the prognosis (P > .05). Patients with high-grade gliomas may have a shorter lifespan (P < .05). In terms of overall survival (OS) and disease specificity, all 3 classical treatments failed to improve the life expectancy (P > .05). In adult patients with GBM, we found that age, tumor grade, surgery, radiotherapy, and chemotherapy were independent risk factors for all-cause mortality. In the univariate disease-specific analysis, age, tumor grade, surgery, radiotherapy, and chemotherapy were independent risk factors. However, in multivariate disease-specific analysis, the results showed that only tumor grade and surgery were independent risk factors for GBM. CONCLUSIONS: Older patients diagnosed with GBM have worse survival, and patients with glioma of higher grades have a shorter lifespan. Age, grade, surgery, radiation therapy, and chemotherapy were independent prognostic factors for patients with GBM.


Assuntos
Glioblastoma , Glioma , Adulto , Humanos , Glioblastoma/terapia , Estudos Retrospectivos , Prognóstico , Análise de Sobrevida
12.
Radiat Oncol ; 17(1): 198, 2022 Dec 02.
Artigo em Inglês | MEDLINE | ID: mdl-36461120

RESUMO

BACKGROUND: Quantitative image analysis based on radiomic feature extraction is an emerging field for survival prediction in oncological patients. 18F-Fluorethyltyrosine positron emission tomography (18F-FET PET) provides important diagnostic and grading information for brain tumors, but data on its use in survival prediction is scarce. In this study, we aim at investigating survival prediction based on multiple radiomic features in glioblastoma patients undergoing radio(chemo)therapy. METHODS: A dataset of 37 patients with glioblastoma (WHO grade 4) receiving radio(chemo)therapy was analyzed. Radiomic features were extracted from pre-treatment 18F-FET PET images, following intensity rebinning with a fixed bin width. Principal component analysis (PCA) was applied for variable selection, aiming at the identification of the most relevant features in survival prediction. Random forest classification and prediction algorithms were optimized on an initial set of 25 patients. Testing of the implemented algorithms was carried out in different scenarios, which included additional 12 patients whose images were acquired with a different scanner to check the reproducibility in prediction results. RESULTS: First order intensity variations and shape features were predominant in the selection of most important radiomic signatures for survival prediction in the available dataset. The major axis length of the 18F-FET-PET volume at tumor to background ratio (TBR) 1.4 and 1.6 correlated significantly with reduced probability of survival. Additional radiomic features were identified as potential survival predictors in the PTV region, showing 76% accuracy in independent testing for both classification and regression. CONCLUSIONS: 18F-FET PET prior to radiation provides relevant information for survival prediction in glioblastoma patients. Based on our preliminary analysis, radiomic features in the PTV can be considered a robust dataset for survival prediction.


Assuntos
Neoplasias Encefálicas , Glioblastoma , Humanos , Glioblastoma/diagnóstico por imagem , Glioblastoma/terapia , Reprodutibilidade dos Testes , Neoplasias Encefálicas/diagnóstico por imagem , Neoplasias Encefálicas/terapia , Tomografia por Emissão de Pósitrons , Oncologia
13.
Front Immunol ; 13: 1003651, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36466873

RESUMO

Glioblastoma multiforme (GBM) is the most malignant intracranial tumor in adults, characterized by extensive infiltrative growth, high vascularization, and resistance to multiple therapeutic approaches. Among the many factors affecting the therapeutic effect, the immunosuppressive GBM microenvironment that is created by cells and associated molecules via complex mechanisms plays a particularly important role in facilitating evasion of the tumor from the immune response. Accumulating evidence is also revealing a close association of the gut microbiota with the challenges in the treatment of GBM. The gut microbiota establishes a connection with the central nervous system through bidirectional signals of the gut-brain axis, thus affecting the occurrence and development of GBM. In this review, we discuss the key immunosuppressive components in the tumor microenvironment, along with the regulatory mechanism of the gut microbiota involved in immunity and metabolism in the GBM microenvironment. Lastly, we concentrate on the immunotherapeutic strategies currently under investigation, which hold promise to overcome the hurdles of the immunosuppressive tumor microenvironment and improve the therapeutic outcome for patients with GBM.


Assuntos
Neoplasias Encefálicas , Glioblastoma , Adulto , Humanos , Glioblastoma/terapia , Fatores Imunológicos , Imunoterapia , Imunossupressores , Neoplasias Encefálicas/terapia , Microambiente Tumoral
14.
Front Immunol ; 13: 1027631, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36532035

RESUMO

Introduction: As a malignant brain tumor, glioblastoma (GBM) is characterized by intratumor heterogeneity, a worse prognosis, and highly invasive, lethal, and refractory natures. Immunotherapy has been becoming a promising strategy to treat diverse cancers. It has been known that there are highly heterogeneous immunosuppressive microenvironments among different GBM molecular subtypes that mainly include classical (CL), mesenchymal (MES), and proneural (PN), respectively. Therefore, an in-depth understanding of immune landscapes among them is essential for identifying novel immune markers of GBM. Methods and results: In the present study, based on collecting the largest number of 109 immune signatures, we aim to achieve a precise diagnosis, prognosis, and immunotherapy prediction for GBM by performing a comprehensive immunogenomic analysis. Firstly, machine-learning (ML) methods were proposed to evaluate the diagnostic values of these immune signatures, and the optimal classifier was constructed for accurate recognition of three GBM subtypes with robust and promising performance. The prognostic values of these signatures were then confirmed, and a risk score was established to divide all GBM patients into high-, medium-, and low-risk groups with a high predictive accuracy for overall survival (OS). Therefore, complete differential analysis across GBM subtypes was performed in terms of the immune characteristics along with clinicopathological and molecular features, which indicates that MES shows much higher immune heterogeneity compared to CL and PN but has significantly better immunotherapy responses, although MES patients may have an immunosuppressive microenvironment and be more proinflammatory and invasive. Finally, the MES subtype is proved to be more sensitive to 17-AAG, docetaxel, and erlotinib using drug sensitivity analysis and three compounds of AS-703026, PD-0325901, and MEK1-2-inhibitor might be potential therapeutic agents. Conclusion: Overall, the findings of this research could help enhance our understanding of the tumor immune microenvironment and provide new insights for improving the prognosis and immunotherapy of GBM patients.


Assuntos
Neoplasias Encefálicas , Glioblastoma , Humanos , Glioblastoma/diagnóstico , Glioblastoma/terapia , Glioblastoma/patologia , Prognóstico , Imunoterapia , Aprendizado de Máquina , Microambiente Tumoral
15.
J Transl Med ; 20(1): 620, 2022 12 26.
Artigo em Inglês | MEDLINE | ID: mdl-36572880

RESUMO

Glioblastoma is the most lethal form of brain tumor with a recurrence rate of almost 90% and a survival time of only 15 months post-diagnosis. It is a highly heterogeneous, aggressive, and extensively studied tumor. Multiple studies have proposed therapeutic approaches to mitigate or improve the survival for patients with glioblastoma. In this article, we review the loss of the 5'-methylthioadenosine phosphorylase (MTAP) gene as a potential therapeutic approach for treating glioblastoma. MTAP encodes a metabolic enzyme required for the metabolism of polyamines and purines leading to DNA synthesis. Multiple studies have explored the loss of this gene and have shown its relevance as a therapeutic approach to glioblastoma tumor mitigation; however, other studies show that the loss of MTAP does not have a major impact on the course of the disease. This article reviews the contrasting findings of MTAP loss with regard to mitigating the effects of glioblastoma, and also focuses on multiple aspects of MTAP loss in glioblastoma by providing insights into the known findings and some of the unexplored areas of this field where new approaches can be imagined for novel glioblastoma therapeutics.


Assuntos
Glioblastoma , Humanos , Glioblastoma/genética , Glioblastoma/terapia , Purina-Núcleosídeo Fosforilase/genética , Purina-Núcleosídeo Fosforilase/metabolismo
17.
Nat Cancer ; 3(12): 1534-1552, 2022 12.
Artigo em Inglês | MEDLINE | ID: mdl-36539501

RESUMO

Recent longitudinal studies of glioblastoma (GBM) have demonstrated a lack of apparent selection pressure for specific DNA mutations in recurrent disease. Single-cell lineage tracing has shown that GBM cells possess a high degree of plasticity. Together this suggests that phenotype switching, as opposed to genetic evolution, may be the escape mechanism that explains the failure of precision therapies to date. We profiled 86 primary-recurrent patient-matched paired GBM specimens with single-nucleus RNA, single-cell open-chromatin, DNA and spatial transcriptomic/proteomic assays. We found that recurrent GBMs are characterized by a shift to a mesenchymal phenotype. We show that the mesenchymal state is mediated by activator protein 1. Increased T-cell abundance at recurrence was prognostic and correlated with hypermutation status. We identified tumor-supportive networks of paracrine and autocrine signals between GBM cells, nonmalignant neuroglia and immune cells. We present cell-intrinsic and cell-extrinsic targets and a single-cell multiomics atlas of GBM under therapy.


Assuntos
Glioblastoma , Humanos , Glioblastoma/genética , Glioblastoma/terapia , Proteômica , Mutação , Prognóstico , Estudos Longitudinais
18.
Sci Adv ; 8(46): eadd2288, 2022 11 16.
Artigo em Inglês | MEDLINE | ID: mdl-36399574

RESUMO

Despite the challenges in treating glioblastomas (GBMs) with immune adjuvants, increasing evidence suggests that targeting the immune cells within the tumor microenvironment (TME) can lead to improved responses. Here, we present a closed-loop controlled, microbubble-enhanced focused ultrasound (MB-FUS) system and test its abilities to safely and effectively treat GBMs using immune checkpoint blockade. The proposed system can fine-tune the exposure settings to promote MB acoustic emission-dependent expression of the proinflammatory marker ICAM-1 and delivery of anti-PD1 in a mouse model of GBM. In addition to enhanced interaction of proinflammatory macrophages within the PD1-expressing TME and significant improvement in survival (P < 0.05), the combined treatment induced long-lived memory T cell formation within the brain that supported tumor rejection in rechallenge experiments. Collectively, our findings demonstrate the ability of MB-FUS to augment the therapeutic impact of immune checkpoint blockade in GBMs and reinforce the notion of spatially tumor-targeted (loco-regional) brain cancer immunotherapy.


Assuntos
Neoplasias Encefálicas , Glioblastoma , Animais , Camundongos , Inibidores de Checkpoint Imunológico/farmacologia , Inibidores de Checkpoint Imunológico/uso terapêutico , Imunoterapia , Neoplasias Encefálicas/terapia , Encéfalo , Fatores Imunológicos , Glioblastoma/terapia , Microambiente Tumoral
20.
Oncoimmunology ; 11(1): 2138152, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36338147

RESUMO

Adoptive transfer of γδ T cells is a novel immunotherapeutic approach to glioblastoma. Few recent studies have shown the efficacy of γδ T cells against glioblastoma, but no previous studies have identified the ligand-receptor interactions between γδ T cells and glioblastoma cells. Here, we identify those ligand-receptor interactions and provide a basis for using γδ T cells to treat glioblastoma. Vγ9Vδ2 T cells were generated from peripheral blood mononuclear cells of healthy donors using artificial antigen presenting cells. MICA, ULBP, PVR and Nectin-2 expression in 10 patient-derived glioblastoma (PDG) cells were analyzed. The in vitro cytokine secretion from the γδ T cells and their cytotoxicity toward the PDG cells were also analyzed. The in vivo anti-tumor effects were evaluated using a U87 orthotopic xenograft glioblastoma model. Expression of ligands and cytotoxicity of the γδ T cells varied among the PDG cells. IFN-γ and Granzyme B secretion levels were significantly higher when γδ Tcells were co-cultured with high-susceptible PDG cells than when they were co-cultured with low-susceptible PDG cells. Cytotoxicity correlated significantly with the expression levels of DNAM-1 ligands of the PDG cells. Blocking DNAM-1 resulted in a decrease in γδ T cell-mediated cytotoxicity and cytokine secretion. Intratumoral injection of γδ T cells showed anti-tumor effects in an orthotopic mouse model. Allogenic γδ T cells showed potent anti-tumor effects on glioblastoma in a DNAM-1 axis dependent manner. Our findings will facilitate the development of clinical strategies using γδ T cells for glioblastoma treatment.


Assuntos
Glioblastoma , Camundongos , Animais , Humanos , Glioblastoma/terapia , Receptores de Antígenos de Linfócitos T gama-delta , Leucócitos Mononucleares/metabolismo , Leucócitos Mononucleares/patologia , Ligantes , Linfócitos T , Citocinas
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