RESUMO
OBJECTIVE: This study was based on MRI features and number of tumor-infiltrating CD8 + T cells in post-operative pathology, in predicting meningioma recurrence risk. METHODS: Clinical, pathological, and imaging data of 102 patients with surgically and pathologically confirmed meningiomas were retrospectively analyzed. Patients were divided into recurrence and non-recurrence groups based on follow-up. Tumor-infiltrating CD8 + T cells in tissue samples were quantitatively assessed with immunohistochemical staining. Apparent diffusion coefficient (ADC) histogram parameters from preoperative MRI were quantified in MaZda. Considering the high correlation between ADC histogram parameters, we only chose ADC histogram parameter that had the best predictive efficacy for COX regression analysis further. A visual nomogram was then constructed and the recurrence probability at 1- and 2-years was determined. Finally, subgroup analysis was performed with the nomogram. RESULTS: The risk factors for meningioma recurrence were ADCp1 (hazard ratio [HR] = 0.961, 95% confidence interval [95% CI]: 0.937 ~ 0.986, p = 0.002) and CD8 + T cells (HR = 0.026, 95%CI: 0.001 ~ 0.609, p = 0.023). The resultant nomogram had AUC values of 0.779 and 0.784 for 1- and 2-years predicted recurrence rates, respectively. The survival analysis revealed that patients with low CD8 + T cells counts or ADCp1 had higher recurrence rates than those with high CD8 + T cells counts or ADCp1. Subgroup analysis revealed that the AUC of nomogram for predicting 1-year and 2-year recurrence of WHO grade 1 and WHO grade 2 meningiomas was 0.872 (0.652) and 0.828 (0.751), respectively. CONCLUSIONS: Preoperative ADC histogram parameters and tumor-infiltrating CD8 + T cells may be potential biomarkers in predicting meningioma recurrence risk. CLINICAL RELEVANCE STATEMENT: The findings will improve prognostic accuracy for patients with meningioma and potentially allow for targeted treatment of individuals who have the recurrent form.
Assuntos
Linfócitos T CD8-Positivos , Linfócitos do Interstício Tumoral , Neoplasias Meníngeas , Meningioma , Recidiva Local de Neoplasia , Nomogramas , Humanos , Meningioma/diagnóstico por imagem , Meningioma/patologia , Meningioma/imunologia , Meningioma/cirurgia , Masculino , Feminino , Recidiva Local de Neoplasia/diagnóstico por imagem , Recidiva Local de Neoplasia/patologia , Pessoa de Meia-Idade , Linfócitos T CD8-Positivos/imunologia , Estudos Retrospectivos , Neoplasias Meníngeas/diagnóstico por imagem , Neoplasias Meníngeas/patologia , Neoplasias Meníngeas/imunologia , Neoplasias Meníngeas/cirurgia , Idoso , Adulto , Imageamento por Ressonância Magnética/métodos , Fatores de Risco , PrognósticoRESUMO
INTRODUCTION: Programmed death-ligand 1 (PD-L1) expression is an immune evasion mechanism that has been demonstrated in many tumors and is commonly associated with a poor prognosis. Over the years, anti-PD-L1 agents have gained attention as novel anticancer therapeutics that induce durable tumor regression in numerous malignancies. They may be a new treatment choice for neurofibromatosis type 2 (NF2) patients. AIMS: The aims of this study were to detect the expression of PD-L1 in NF2-associated meningiomas, explore the effect of PD-L1 downregulation on tumor cell characteristics and T-cell functions, and investigate the possible pathways that regulate PD-L1 expression to further dissect the possible mechanism of immune suppression in NF2 tumors and to provide new treatment options for NF2 patients. RESULTS: PD-L1 is heterogeneously expressed in NF2-associated meningiomas. After PD-L1 knockdown in NF2-associated meningioma cells, tumor cell proliferation was significantly inhibited, and the apoptosis rate was elevated. When T cells were cocultured with siPD-L1-transfected NF2-associated meningioma cells, the expression of CD69 on both CD4+ and CD8+ T cells was partly reversed, and the capacity of CD8+ T cells to kill siPD-L1-transfected tumor cells was partly restored. Results also showed that the PI3K-AKT-mTOR pathway regulates PD-L1 expression, and the mTOR inhibitor rapamycin rapidly and persistently suppresses PD-L1 expression. In vivo experimental results suggested that anti-PD-L1 antibody may have a synergetic effect with the mTOR inhibitor in reducing tumor cell proliferation and that reduced PD-L1 expression could contribute to antitumor efficacy. CONCLUSIONS: Targeting PD-L1 could be helpful for restoring the function of tumor-infiltrating lymphocytes and inducing apoptosis to inhibit tumor proliferation in NF2-associated meningiomas. Dissecting the mechanisms of the PD-L1-driven tumorigenesis of NF2-associated meningioma will help to improve our understanding of the mechanisms underlying tumor progression and could facilitate further refinement of current therapies to improve the treatment of NF2 patients.
Assuntos
Antígeno B7-H1 , Proliferação de Células , Neoplasias Meníngeas , Meningioma , Neurofibromatose 2 , Linfócitos T , Meningioma/metabolismo , Meningioma/imunologia , Meningioma/patologia , Humanos , Antígeno B7-H1/metabolismo , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/fisiologia , Neoplasias Meníngeas/metabolismo , Neoplasias Meníngeas/patologia , Neoplasias Meníngeas/imunologia , Animais , Linfócitos T/metabolismo , Linfócitos T/efeitos dos fármacos , Neurofibromatose 2/metabolismo , Camundongos , Masculino , Feminino , Neurofibromina 2/metabolismo , Neurofibromina 2/genética , Linhagem Celular Tumoral , Pessoa de Meia-Idade , Camundongos Nus , Apoptose/efeitos dos fármacos , Apoptose/fisiologiaRESUMO
AIM: To investigate the status of immune checkpoint molecules (CTLA-4 and TIM-3) in meningiomas and thus contribute to the development of new personalized treatment strategies. MATERIAL AND METHODS: We utilized 402 cases of meningioma for this study. New blocks were prepared using the tissue microarray method, and sections obtained from these blocks were immunohistochemically stained with CTLA-4 and TIM-3 antibodies. Subsequently, statistical analysis were performed. RESULTS: Our findings revealed that CTLA-4 expression were observed in 25.1% of meningiomas. CTLA-4 expression and the number of expressing lymphocytes were found to be significantly higher in high-grade tumors and in those with brain invasion. Meningiomas with staining of immune cells with TIM-3 are 3.5%, and the tumor grade was correlated with the number of immune cells expressing TIM-3. CONCLUSION: Immune checkpoint molecules (CTLA-4 and TIM-3) with varying levels of expression can serve as prognostic and predictive biomarkers, as well as important targets for therapy. Drugs developed for CTLA-4 and TIM-3 molecules may prove to be more effective in treating meningiomas with high-grade, brain-invading, spontaneous necrosis, and macronucleolus.
Assuntos
Antígeno CTLA-4 , Receptor Celular 2 do Vírus da Hepatite A , Imuno-Histoquímica , Neoplasias Meníngeas , Meningioma , Humanos , Meningioma/imunologia , Meningioma/patologia , Meningioma/metabolismo , Masculino , Neoplasias Meníngeas/imunologia , Neoplasias Meníngeas/patologia , Neoplasias Meníngeas/metabolismo , Feminino , Pessoa de Meia-Idade , Antígeno CTLA-4/metabolismo , Antígeno CTLA-4/imunologia , Receptor Celular 2 do Vírus da Hepatite A/metabolismo , Idoso , Adulto , Biomarcadores Tumorais/metabolismo , Proteínas de Checkpoint Imunológico/metabolismo , Idoso de 80 Anos ou mais , Adulto Jovem , AdolescenteRESUMO
Meningioma is a prevalent intracranial malignancy known for its aggressive growth. Circular RNAs (circRNAs) play a crucial role in the development of various cancers. However, their involvement in meningioma remains understudied. This study aimed to investigate the function and underlying mechanism of hsa_circ_0004872 in meningioma. The molecular expression of hsa_circ_0004872, PD-L1 and EIF4A3 was identified by RT-qPCR and/or western blot assays. Cell viability, migration, and invasion were assessed through CCK-8 and Transwell assays, respectively. Cytotoxicity was determined using an LDH assay, and cell apoptosis was monitored by flow cytometry. The RNA and protein interactions were assessed through RNA-protein immunoprecipitation (RIP) and RNA pull down analyses. Our findings revealed that hsa_circ_0004872 expression was significantly downregulated in both meningioma tissue samples and cells. Overexpression of hsa_circ_0004872 inhibited the proliferation, metastasis, and immune escape of meningioma cells, as well as enhanced the cytotoxicity of CD8+ T cells by suppressing PD-L1. Furthermore, hsa_circ_0004872 directly interacted with EIF4A3, leading to the degradation of PD-L1 mRNA. Finally, inhibiting EIF4A3 improved the proliferation, metastasis, and immune escape of meningioma cells, as well as the cytotoxicity of CD8+ T cells. Our study demonstrated that hsa_circ_0004872 mitigated the proliferation, metastasis,and immune escape of meningioma cells by targeting the EIF4A3/PD-L1 axis. These findings suggested that hsa_circ_0004872 and EIF4A3 might serve as promising biological markers and therapeutic targets for meningioma treatment.
Assuntos
Antígeno B7-H1 , Proliferação de Células , Fator de Iniciação 4A em Eucariotos , Neoplasias Meníngeas , Meningioma , RNA Circular , Meningioma/patologia , Meningioma/imunologia , Meningioma/genética , Meningioma/metabolismo , Humanos , Antígeno B7-H1/metabolismo , Antígeno B7-H1/genética , RNA Circular/genética , Neoplasias Meníngeas/patologia , Neoplasias Meníngeas/genética , Neoplasias Meníngeas/imunologia , Neoplasias Meníngeas/metabolismo , Fator de Iniciação 4A em Eucariotos/genética , Fator de Iniciação 4A em Eucariotos/metabolismo , Linhagem Celular Tumoral , Regulação Neoplásica da Expressão Gênica , Movimento Celular , Evasão Tumoral , Apoptose , RNA Helicases DEAD-boxRESUMO
BACKGROUND: Blood transfusion necessity in neurosurgery varies based on surgical type, blood loss, and patient anemia. Leukocytes in red blood cells (RBCs) component release pro-inflammatory cytokines during storage, contributing to transfusion-related immunomodulation (TRIM). Our aim was to examine the impact of the leukocyte content in transfused PRBCs on patients undergoing neurosurgery for meningioma tumours. STUDY DESIGN AND METHODS: This prospective randomized controlled trial conducted from 2018 to 2020 by dividing patients randomly into non-leukoreduced (NLR) (n = 65) and leuko-reduced (LR) (n = 65) groups based on PRBCs received during surgery and hospital stay. Hospital and ICU stays, mechanical ventilation duration, and postoperative bacterial infections were observed. Hematological parameters and cytokine levels (IL-10, INF-gamma, and FAS-L) were assessed at pre-transfusion, 24 h, and 7 days post-transfusion. Data analysis included Mann-Whitney U test, Friedman test, Fisher's chi-square test, with statistical significance at p < 0.05. RESULTS: In our study, ICU and hospital stay duration showed no significant difference (p = 0.06) between groups. However, NLR group had longer mean mechanical ventilation (18 ± 40.1 h) than the LR group (12.8 ± 8.6 h). Both groups showed statistically significant increase in Fas-L level on days 1 and 7 (p < 0.05). The IL-10 levels rose 43% in the NLR group, while and decreased by 7% the LR group on day 1. On day 7, IL-10 increased by 75% in NLR and decreased by 40% in LR, with no significance (p > 0.05). CONCLUSION: In conclusion, leukoreduction appeared to offer some immune response protection in term of reducing mechanical ventilation timings and cytokine level changes.
Assuntos
Meningioma , Humanos , Feminino , Masculino , Pessoa de Meia-Idade , Meningioma/imunologia , Meningioma/terapia , Meningioma/sangue , Estudos Prospectivos , Idoso , Adulto , Imunomodulação , Neoplasias Meníngeas/terapia , Neoplasias Meníngeas/imunologia , Neoplasias Meníngeas/sangueRESUMO
BACKGROUND: To identify candidate key genes and pathways related to resting mast cells in meningioma and the underlying molecular mechanisms of meningioma. METHODS: Gene expression profiles of the used microarray datasets were obtained from the Gene Expression Omnibus (GEO) database. GO and KEGG pathway enrichments of DEGs were analyzed using the ClusterProfiler package in R. The protein-protein interaction network (PPI), and TF-miRNA- mRNA co-expression networks were constructed. Further, the difference in immune infiltration was investigated using the CIBERSORT algorithm. RESULTS: A total of 1499 DEGs were identified between tumor and normal controls. The analysis of the immune cell infiltration landscape showed that the probability of distribution of memory B cells, regulatory T cells (Tregs), and resting mast cells in tumor samples were significantly higher than those in the controls. Moreover, through WGCNA analysis, the module related to resting mast cells contained 158 DEGs, and KEGG pathway analysis revealed that the DEGs were dominant in the TNF signaling pathway, cytokine-cytokine receptor interaction, and IL-17 signaling pathway. Survival analysis of hub genes related to resting mast cells showed that the risk model was constructed based on 9 key genes. The TF-miRNA- mRNA co-regulation network, including MYC-miR-145-5p, TNFAIP3-miR-29c-3p, and TNFAIP3-hsa-miR-335-3p, were obtained. Further, 36 nodes and 197 interactions in the PPI network were identified. CONCLUSION: The results of this study revealed candidate key genes, miRNAs, and pathways related to resting mast cells involved in meningioma development, providing potential therapeutic targets for meningioma treatment.
Assuntos
Perfilação da Expressão Gênica , Mastócitos/citologia , Neoplasias Meníngeas/genética , Meningioma/genética , Algoritmos , Bases de Dados Genéticas , Humanos , Imunidade Celular , Interleucina-17/metabolismo , Células B de Memória/citologia , Neoplasias Meníngeas/imunologia , Neoplasias Meníngeas/patologia , Meningioma/imunologia , Meningioma/patologia , MicroRNAs/metabolismo , Mapas de Interação de Proteínas , Transdução de Sinais , Linfócitos T Reguladores/citologiaRESUMO
IgG4-related inflammatory pseudotumors are very uncommon and are characterized histologically by the presence of inflammatory swellings with increasing IgG4-positive plasma cells and lymphocytes infiltrating the tissues. As reports of intracranial IgG4-related pseudotumors are very rare, we report a case of an IgG4-related inflammatory pseudotumor involving the clivus mimicking meningioma. A 46-year-old male presented with intermittent headache for 2 years and a sudden onset of dysphagia and dysphonia of 7 days' duration along with lower limb weakness. Enhanced magnetic resonance imaging (MRI) of the skull base revealed an isointense signal on T1- and T2-weighted images from an enhanced mass located at the middle of the upper clivus region, for which a meningioma was highly suspected. Then, an endoscopic transsphenoidal approach was adopted and the lesion was partially resected, as the subdural extra-axial lesion was found to be very tough and firm, exhibiting fibrous scarring attaching to the brain stem and basal artery. After the surgery, brain stem and posterior cranial nerve decompression was achieved, and the patient's symptoms, such as dysphagia, dysphonia and lower limb weakness, improved. Pathological findings showed many IgG4-positive plasma cells and lymphocytes surrounded by collagen-rich fibers. The patient was sent to the rheumatology department for further glucocorticoids after the diagnosis of an IgG4-related inflammatory pseudotumor was made. This case highlights the importance of considering IgG4-related inflammatory pseudotumors as a differential diagnosis in patients with lesions involving the clivus presenting with a sudden onset of symptoms of dysphagia and dysphonia along with lower limb weakness when other more threatening causes have been excluded. IgG4-related inflammatory pseudotumors are etiologically enigmatic and unpredictable, and total resection might not be warranted. Glucocorticoids are usually the first line of treatment after diagnosis.
Assuntos
Fossa Craniana Posterior/patologia , Granuloma de Células Plasmáticas/diagnóstico , Imunoglobulina G/imunologia , Inflamação/patologia , Neoplasias Meníngeas/diagnóstico , Meningioma/diagnóstico , Fossa Craniana Posterior/imunologia , Diagnóstico Diferencial , Granuloma de Células Plasmáticas/imunologia , Granuloma de Células Plasmáticas/cirurgia , Humanos , Inflamação/imunologia , Masculino , Neoplasias Meníngeas/imunologia , Neoplasias Meníngeas/cirurgia , Meningioma/imunologia , Meningioma/cirurgia , Pessoa de Meia-Idade , PrognósticoAssuntos
Imunoglobulina G , Neoplasias Meníngeas/diagnóstico , Meningioma/diagnóstico , Meningite/diagnóstico , Fossa Craniana Posterior , Humanos , Imageamento por Ressonância Magnética , Masculino , Neoplasias Meníngeas/diagnóstico por imagem , Neoplasias Meníngeas/imunologia , Meningioma/diagnóstico por imagem , Meningioma/imunologia , Meningite/diagnóstico por imagem , Meningite/imunologia , Pessoa de Meia-IdadeRESUMO
BACKGROUND: The tumor microenvironment is an emerging biomarker of underlying genomic heterogeneity and response to immunotherapy-based treatment regimens in solid malignancies. How tumor mutational burden influences the density, distribution, and presence of a localized immune response in meningiomas is unknown. METHODS: Representative hematoxylin and eosin slides were reviewed at 40X to assess for the density of inflammatory cells. Lymphocytes and macrophages were quantified in the following ordinal manner: 0 = not present, 1 = 1-25 cells present, and 2 = greater than 26 cells present. Immune cell infiltrate grade was scored for both scattered and aggregated distributions. Next generation targeted sequencing was performed on all meningiomas included in this study. RESULTS: One hundred and forty-five meningiomas were evaluated in this study. Lymphocytes were observed in both scattered (95.9%) and aggregated (21.4%) distributions. A total of 115 (79.3%) meningiomas had 1-25 scattered lymphocytes, and 24 (16.6%) had > 25 scattered lymphocytes, and 6 (4.1%) had no scattered lymphocytes. Twenty (13.8%) meningiomas had 1-25 aggregated lymphocytes. Eleven (7.6%) had > 25 aggregated lymphocytes and 114 (78.6%) had no aggregated lymphocytes. Six (4.1%) meningiomas had 1-25 aggregated macrophages, 5 (3.4%) had > 25 aggregated macrophages, and 134 (92.4%) had no aggregated macrophages. Density of aggregated lymphocytes and aggregated macrophages were associated with higher tumor grade, P = 0.0071 and P = 0.0068, respectively. Scattered lymphocyte density was not associated with meningioma grade. The presence of scattered lymphocytes was associated with increased tumor mutational burden. Meningiomas that did not have scattered lymphocytes had a mean number of single mutations of 2.3 ± 2.9, compared with meningiomas that had scattered lymphocytes, 6.9 ± 20.3, P = 0.03. NF2 mutations were identified in 59 (40.7%) meningiomas and were associated with increased density of scattered lymphocytes. NF2 mutations were seen in 0 (0%) meningiomas that did not have scattered lymphocytes, 46 (40.0%) meningiomas that had 1-25 scattered lymphocytes, and 13 (54.2%) meningiomas that had > 25 scattered lymphocytes, P = 0.046. CONCLUSIONS: Our findings suggest that distribution of immune cell infiltration in meningiomas is associated with tumor mutational burden. NF2 mutational status was associated with an increasing density of scattered lymphocytes. As the role of immunotherapy in meningiomas continues to be elucidated with clinical trials that are currently underway, these results may serve as a novel biomarker of tumor mutational burden in meningiomas.
Assuntos
Neoplasias Meníngeas/genética , Meningioma/genética , Mutação/genética , Neurofibromina 2/genética , Microambiente Tumoral/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/imunologia , Feminino , Genômica/métodos , Humanos , Linfócitos/imunologia , Macrófagos/imunologia , Masculino , Neoplasias Meníngeas/imunologia , Meningioma/imunologia , Pessoa de Meia-Idade , Mutação/imunologia , Neurofibromina 2/imunologia , Microambiente Tumoral/imunologia , Adulto JovemRESUMO
BACKGROUND: Properties of the inflammatory tumor microenvironment are associated with disease subtype, grade, and prognosis in various cancer entities. As immune-modulatory therapies are currently being explored in patients with meningeal neoplasms, we investigated their inflammatory microenvironment (meningiomas and solitary fibrous tumor/hemangiopericytoma (SFT/HPC)). MATERIALS AND METHODS: 74 meningeal tumor specimens: (10/74 (13.5%) atypical meningioma; 8/74 (10.8%) anaplastic meningioma; 8/74 (10.8%) chordoid meningioma; 9/74 (12.2%) fibroblastic meningioma; 10/74 (13.5%) transitional meningioma; 3/74 (4.1%) rhabdoid meningioma; 7/74 (9.5%) meningothelial meningioma; SFT/HPC (19/74 (25.7%) were retrieved from the Neuro-Biobank, Medical University of Vienna, Austria. RESULTS: Tumor-infiltrating lymphocyte (TIL) infiltration could be observed in the majority of the investigated specimens (CD3+: 66/74 (89.2%); CD8+: 47/74 (63.5%); CD45RO+: 29/73 (39.2%); FOXP3+ 19/74 (25.7%); PD1+: 3/74 (4.1%). No difference in TIL infiltration was observed between SFT/HPC and meningioma cases. Higher density of FOXP3+ TILs was observed with increasing WHO grade in meningioma specimens (p = 0.005). Membranous programmed cell death ligand 1 (PD-L1) expression was observed in 4/74 (5.4%) specimens, with 3/74 (4.1%) presenting with 1% and 1/74 (1.4%) with 3% PD-L1 expressing tumor cells. Lymphatic vessels as identified by podoplanin immunohistochemistry were observed in 10/74 (13.5%) specimens and were significantly associated with presence of membranous PD-L1 expression on tumor cells (p = 0.003). CONCLUSION: Infiltration by various TIL subtypes can be observed in the majority of meningeal neoplasms, with enrichment of FOXP3-positive regulatory T-cells in higher-grade meningioma. PD-L1 expression on tumor cells was only infrequently found. A better understanding of the pathobiological role of the immune system in meningeal neoplasms may facilitate development of immunomodulatory treatment approaches in meningeal tumors.
Assuntos
Fatores de Transcrição Forkhead/metabolismo , Neoplasias Meníngeas/patologia , Meningioma/patologia , Microambiente Tumoral/imunologia , Adulto , Idoso , Antígeno B7-H1/metabolismo , Biomarcadores Tumorais/análise , Hemangiopericitoma/imunologia , Hemangiopericitoma/patologia , Humanos , Linfócitos do Interstício Tumoral/imunologia , Linfócitos do Interstício Tumoral/metabolismo , Linfócitos do Interstício Tumoral/patologia , Masculino , Neoplasias Meníngeas/imunologia , Meningioma/imunologia , Pessoa de Meia-Idade , Tumores Fibrosos Solitários/patologiaRESUMO
PURPOSE OF REVIEW: Our understanding of the genetic and epigenetic alterations in meningioma and the underlying tumor biology of meningioma has significantly changed over the past decade and resulted in revision of prognostically relevant meningioma subclasses within and beyond the WHO classification of CNS tumors. RECENT FINDINGS: The 2016 WHO classification of CNS tumors recognizes WHO grade I, II, and III based on histopathological features. Recent work has identified genetic alterations with prognostic implications, including mutations of the TERT promoter, loss of function of the DMD gene, and inactivation of the tumor suppressor BAP-1. Studies of DNA methylation patterns in meningiomas have resulted in a novel and prognostically relevant meningioma subclassification schema. There have been major advances in our understanding of prognostically relevant genetic and epigenetic changes in meningioma which will hopefully allow for improvement in clinical trial design and the development of more effective therapies for meningioma.
Assuntos
Neoplasias Meníngeas/genética , Meningioma/genética , Variações do Número de Cópias de DNA , Metilação de DNA , Humanos , Neoplasias Meníngeas/classificação , Neoplasias Meníngeas/imunologia , Neoplasias Meníngeas/terapia , Meningioma/classificação , Meningioma/imunologia , Meningioma/terapia , Mutação , Neurofibromina 2/genética , Fosfatidilinositol 3-Quinases/fisiologia , Transdução de Sinais/fisiologia , Microambiente TumoralRESUMO
Modulation of tumor microenvironment is an emerging frontier for new therapeutics. However in meningiomas, the most frequent adult brain tumor, the correlation of microenvironment with tumor phenotype is scarcely studied. We applied a variety of systems biology approaches to bulk tumor transcriptomics to explore the immune environments of both skull base and convexity (hemispheric) meningiomas. We hypothesized that the more benign biology of skull base meningiomas parallels the relative composition and activity of immune cells that oppose tumor growth and/or survival. We firstly applied gene co-expression networks to tumor bulk transcriptomics from 107 meningiomas (derived from 3 independent studies) and found immune processes to be the sole biological mechanism correlated with anatomical location while correcting for tumour grade. We then derived tumor immune cell fractions from bulk transcriptomics data and examined the immune cell-cytokine interactions using a network-based approach. We demonstrate that oncolytic Gamma-Delta T cells dominate skull base meningiomas while mast cells and neutrophils, known to play a role in oncogenesis, show greater activity in convexity tumors. Our results are the first to suggest the importance of tumor microenvironment in meningioma biology in the context of anatomic location and immune landscape. These findings may help better inform surgical decision making and yield location-specific therapies through modulation of immune microenvironment.
Assuntos
Expressão Gênica/imunologia , Neoplasias Meníngeas/imunologia , Meningioma/imunologia , Neoplasias da Base do Crânio/imunologia , Encéfalo/imunologia , Encéfalo/patologia , Neoplasias Encefálicas/imunologia , Neoplasias Encefálicas/patologia , Feminino , Humanos , Masculino , Neoplasias Meníngeas/patologia , Meningioma/patologia , Gradação de Tumores , Neutrófilos/imunologia , Base do Crânio/imunologia , Base do Crânio/patologia , Neoplasias da Base do Crânio/patologia , Linfócitos T/imunologia , Transcriptoma/imunologia , Microambiente Tumoral/imunologiaRESUMO
Tumor-infiltrating immune cells play a decisive part in prognosis and survival. Until now, previous researches have not made clear about the diversity of cell types involved in the immune response. The objective of this work was to confirm the composition of tumor-infiltrating immune cells and their correlation with prognosis in meningiomas based on a metagene approach (known as CIBERSORT) and online databases. A total of 22 tumor-infiltrating immune cells were detected to determine the relationship between the immune infiltration pattern and survival. The proportion of M2 macrophages was more abundant in 68 samples, reaching more than 36%. Univariate Cox regression analysis displayed that the proportion of dendritic cells was obviously related to prognosis. Hierarchical clustering analysis identified two clusters by the method of within sum of squares errors, which exhibited different infiltrating immune cell composition and survival. To summarize, our results indicated that proportions of tumor-infiltrating immune cells as well as cluster patterns were associated with the prognosis, which offered clinical significance for research of meningiomas.
Assuntos
Células Dendríticas/imunologia , Neoplasias Meníngeas/imunologia , Meningioma/imunologia , Macrófagos Associados a Tumor/imunologia , Biomarcadores Tumorais/genética , Bases de Dados Genéticas , Perfilação da Expressão Gênica , Humanos , Imunofenotipagem , Neoplasias Meníngeas/genética , Neoplasias Meníngeas/mortalidade , Neoplasias Meníngeas/terapia , Meningioma/genética , Meningioma/mortalidade , Meningioma/terapia , Fenótipo , Prognóstico , Medição de Risco , Fatores de Risco , Transcriptoma , Microambiente TumoralRESUMO
Meningiomas are the most common adult primary tumor of the central nervous system, but there are no known effective medical therapies for recurrent meningioma, particularly for World Health Organization grade II and III tumors. Meningiomas arise from the meninges, located outside the blood-brain barrier, and therefore may be directly targeted by antibody-mediated immunotherapy. We found that programmed cell death ligand 1 (PD-L1) was highly expressed in multiple human malignant meningioma cell lines and patient tumor samples. PD-L1 was targeted with the anti-PD-L1 antibody avelumab and directed natural killer cells to mediate antibody-dependent cellular cytotoxicity (ADCC) of PD-L1-expressing meningioma tumors both in vitro and in vivo. ADCC of meningioma cells was significantly increased in target cells that upregulated PD-L1 expression and, conversely, abrogated in tumor cells that were depleted of PD-L1. Additionally, the high-affinity natural killer cell line, haNK, outperformed healthy donor NK cells in meningioma ADCC. Together, these data support a clinical trial designed to target PD-L1 with avelumab and haNK cells, potentially offering a novel immunotherapeutic approach for patients with malignant meningioma.
Assuntos
Anticorpos Monoclonais Humanizados/farmacologia , Citotoxicidade Celular Dependente de Anticorpos/efeitos dos fármacos , Imunoterapia/métodos , Células Matadoras Naturais/transplante , Neoplasias Meníngeas/terapia , Meningioma/terapia , Animais , Anticorpos Monoclonais Humanizados/uso terapêutico , Antígeno B7-H1/antagonistas & inibidores , Antígeno B7-H1/genética , Antígeno B7-H1/imunologia , Linhagem Celular Tumoral , Feminino , Técnicas de Silenciamento de Genes , Humanos , Células Matadoras Naturais/efeitos dos fármacos , Células Matadoras Naturais/imunologia , Neoplasias Meníngeas/imunologia , Meningioma/imunologia , Camundongos , Resultado do Tratamento , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Atypical meningiomas with a mixed glial-epithelial phenotype are rare reports, and here we described an aggressive case on which double immunofluorescence ascertained the co-expression of epithelial membrane antigen (EMA) with glial fibrillary acidic protein (GFAP) in the same tumor cells. A 62-year-old female presented with acute intracranial hypertension symptoms occurred over the last 24 hours, muscle weakness on the right side, cerebellar dysarthria, and wide base gate. Magnetic resonance imaging (MRI) examination showed a right cerebellar hemisphere non-homogenous tumor, with intense gadophylia, diffuse contours, and necrotic inner areas. There were also scar-like areas at the level of the left cerebellar hemisphere, and the patient recalled a previous surgical intervention at the age of 6 years old without further diagnostic data. The patient suffered an ischemic event in the brain stem and died shortly after the surgical removal of the tumor. Histopathology revealed an epithelial-like tumor with moderately pleomorphic and elongated cells arranged in fascicles, rare necrotic areas, and a few proliferating multilayered vessels structures. Immunohistochemistry (IHC) revealed variable EMA positivity, intense vimentin staining, rare GFAP-positive intra-tumor areas, a moderate expression for cytokeratin 8/18, reduced labeling for an anti-progesterone receptor (PrgR) antibody, cluster of differentiation (CD) 10 negativity, and a high Ki-67 proliferating index of around 40%. The case was deemed as an atypical meningioma, and interestingly, a double IHC for GFAP∕EMA revealed a strong colocalization of the two markers in the tumor mass. Although extremely rare, the reports of meningiomas expressing a mixed epithelial∕glial profile might be connected with their aggressive evolution. Double IHC might help in predicting the evolution of these cases and determine which patients should benefit from closer surveillance.
Assuntos
Imuno-Histoquímica/métodos , Meningioma/imunologia , Feminino , Humanos , Meningioma/patologia , Pessoa de Meia-IdadeRESUMO
PURPOSE: Clinically aggressive meningiomas (MGMs) are rare but treatment-resistant tumors in need for more effective therapies. Because tumor-infiltrating T lymphocytes (TILs) are essential for successful immunotherapy, we assessed TIL numbers and their activation status in primary (p-) and recurrent (r-) meningiomas and their impact on survival. EXPERIMENTAL DESIGN: Presence of TILs was analyzed in 202 clinically well-annotated cases (n = 123 pMGMs and n = 79 rMGMs) focusing on higher-grade meningiomas [n = 97 World Health Organization (WHO) °II, n = 62 WHO°III]. TILs were quantified by a semiautomated analysis on whole-tissue sections stained by multicolor immunofluorescence for CD3, CD8, FOXP3, and programmed cell death protein 1 (PD-1). RESULTS: Median T-cell infiltration accounted for 0.59% TILs per total cell count. Although there were no significant WHO°-dependent changes regarding helper (CD3+CD8-FOXP3-) and cytotoxic (CD3+CD8+FOXP3-) TILs in pMGMs, higher number of cytotoxic TILs were associated with an improved progression-free survival (PFS) independent of prognostic confounders. rMGMs were characterized by lower numbers of TILs in general, helper, and cytotoxic TILs. The additional analysis of their activation status revealed that a proportion of PD-1+CD8+ TILs within the TIL population was significantly decreased with higher WHO grade and in rMGMs. Furthermore, lower proportions of PD-1+CD8+ TILs were associated with inferior PFS in multivariate analyses, arguing for PD-1 as activation rather than exhaustion marker. CONCLUSIONS: We identified higher numbers of CD3+CD8+FOXP3- TILs and proportions of PD-1-expressing CD3+CD8+FOXP3- TILs as novel biomarkers for better survival. These findings might facilitate the selection of patients who may benefit from immunotherapy and argue in favor of an intervention in primary rather than recurrent tumors.
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Imunoterapia/métodos , Linfócitos do Interstício Tumoral/imunologia , Neoplasias Meníngeas/imunologia , Meningioma/imunologia , Recidiva Local de Neoplasia/imunologia , Linfócitos T Citotóxicos/imunologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/imunologia , Feminino , Humanos , Ativação Linfocitária , Linfócitos do Interstício Tumoral/patologia , Masculino , Neoplasias Meníngeas/patologia , Neoplasias Meníngeas/terapia , Meningioma/patologia , Meningioma/terapia , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/patologia , Recidiva Local de Neoplasia/terapia , Prognóstico , Taxa de Sobrevida , Linfócitos T Citotóxicos/patologia , Adulto JovemRESUMO
AIMS: Skull base meningiomas represent approximately 25% of all meningiomas, nearly 20% of which are atypical or anaplastic. To date, effective medical treatments for meningiomas are still lacking. Genetic aberrations (TRAF7, KLF4, AKT1, and SMO) and the effects of genetic aberrations on the expression of inhibitory immune checkpoint molecules (PD-L1, IDO, and TDO2) in skull base meningiomas are still unclear. METHODS: Genetic alterations in the four genes were identified in 92 skull base meningiomas by Sanger sequencing. The expression differences in immune checkpoints between mutant and wild-type (WT) tumors were determined by immunohistochemistry (IHC) and Western blot (WB). RESULTS: The four mutations were not concurrently detected in the patients with skull base meningiomas. Among the tumors from the KLF4-mutated group, almost half were petroclival meningiomas. KLF4- and TRAF7-mutated tumors were predominantly secretory meningiomas. SMO-mutated tumors exhibited higher calcification, and half of these tumors were observed in the brain midline. Receiver operating characteristic curve analysis indicated that tumor volume can predict KLF4 and TRAF7 mutation status with high sensitivity and specificity, respectively. The IHC and WB analyses indicated that PD-L1, IDO, and TDO2 levels in tumors with TRAF7 mutations were significantly higher than those in WT tumors. Meanwhile, there was a significant difference in TDO2 between tumors with AKT1 mutations and WT tumors. Specifically, TRAF7 mutations could play a key role in skull base meningiomas by regulating the expression of inhibitory immune checkpoints and thus suppressing immune responses. CONCLUSIONS: Checkpoint inhibitors may be potential strategies for targeted immunotherapies of these mutant meningiomas.
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Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Regulação Neoplásica da Expressão Gênica , Neoplasias Meníngeas/patologia , Meningioma/patologia , Mutação , Neoplasias da Base do Crânio/patologia , Adolescente , Adulto , Idoso , Antígeno B7-H1/genética , Antígeno B7-H1/metabolismo , Feminino , Seguimentos , Humanos , Indolamina-Pirrol 2,3,-Dioxigenase/genética , Indolamina-Pirrol 2,3,-Dioxigenase/metabolismo , Fator 4 Semelhante a Kruppel , Fatores de Transcrição Kruppel-Like/genética , Fatores de Transcrição Kruppel-Like/metabolismo , Masculino , Neoplasias Meníngeas/genética , Neoplasias Meníngeas/imunologia , Neoplasias Meníngeas/metabolismo , Meningioma/genética , Meningioma/imunologia , Meningioma/metabolismo , Pessoa de Meia-Idade , Prognóstico , Proteínas Proto-Oncogênicas c-akt/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo , Curva ROC , Neoplasias da Base do Crânio/genética , Neoplasias da Base do Crânio/imunologia , Neoplasias da Base do Crânio/metabolismo , Receptor Smoothened/genética , Receptor Smoothened/metabolismo , Triptofano Oxigenase/genética , Triptofano Oxigenase/metabolismo , Peptídeos e Proteínas Associados a Receptores de Fatores de Necrose Tumoral/genética , Peptídeos e Proteínas Associados a Receptores de Fatores de Necrose Tumoral/metabolismo , Adulto JovemRESUMO
OBJECTIVES: It is difficult to treat cavernous sinus (CS) meningiomas because of their complex vascular and neurological structures. Recently, immunotherapy has become an attractive therapeutic modality, but the role of tumor immune microenvironment is yet to be investigated for CS meningiomas. In the current study, these molecular and histopathological characteristics were examined in CS meningiomas. METHODS: The present study used twenty-eight meningioma tissues arising in two different locations (8 CS and 20 convexity meningiomas). Immunohistochemical analyses were performed with CD3, CD4, CD8, Foxp3, CD163, PDGFR-ß, VEGF receptors 1 & 2 (VEGFR-1, VEGFR-2), VEGF-A and HIF-1α. Quantitative polymerase chain reaction (qPCR) was performed to assess the expression of Foxp3, VEGF-A, CD163, VEGFRs-1 & 2 and HIF-1α. RESULTS: The numbers of different tumor-infiltrating immune cells, such as immunosuppressive cells, were significantly lower in CS meningiomas compared with convexity meningiomas. Analysis of the vascular characteristics showed the vessels in the CS meningiomas were covered with PDGFR-ß-positive pericytes and were negative or had only very low amounts of VEGFR-1 and VEGFR-2. However, most vessels in convexity meningiomas showed high VEGFRs expression and were not covered with pericytes. Immunohistochemical and qPCR analyses revealed that the expression of HIF-1α, VEGF-A and VEGFRs-1 & 2 was lower in CS meningiomas. CONCLUSION: Fewer immunocompetent cells were observed in CS meningiomas compared with convexity meningiomas. Lower expression of VEGF-A, VEGFRs-1 and 2, and the vascular structure may contribute to this specific immune microenvironment.
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Neoplasias Meníngeas/imunologia , Neoplasias Meníngeas/patologia , Meningioma/imunologia , Meningioma/patologia , Neovascularização Patológica/patologia , Seio Cavernoso/patologia , Humanos , Microambiente Tumoral/imunologiaRESUMO
AIM: Despite current treatments, high-grade meningiomas continue to have a poor prognosis. Immunotherapy targeting immune checkpoints, such as PD-L1, has demonstrated significant success in controlling numerous malignancies. In this study, we investigate the extent of systemic and local immunosuppression in meningiomas to assess the potential benefit of immune checkpoint inhibitors for the treatment of high-grade meningiomas. METHODS: Peripheral blood was collected from patients undergoing resection of meningiomas (WHO grade I, n = 18; grade II, n = 25; grade III, n = 10). Immunosuppressive myeloid cells (CD45+CD11b+PD-L1+), myeloid-derived suppressor cells (MDSCs) (CD11b+CD33+HLA-DRlow), and regulatory T cells (Tregs) (CD3+CD4+CD25+FoxP3+) were quantified through flow cytometry. Tissue sections from the same patients were assessed for PD-L1 expression and T cell infiltration via immunohistochemistry. RESULTS: Patients with grade III meningiomas demonstrated increased peripheral monocyte PD-L1 compared to patients with grade I/II meningiomas and healthy controls. Peripheral MDSC abundance was increased in grades II and III meningioma patients. PD-L1 staining of meningioma tissue demonstrated increased positivity in grade III meningiomas. Intratumoral PD-L1 was not associated with progression-free survival. High-grade meningiomas had increased T-cell infiltration. However, a significant proportion of these T cells were exhausted PD1+ T cells and immunosuppressive Tregs. CONCLUSIONS: Patients with meningiomas exhibit signs of peripheral immunosuppression, including increased PD-L1 on myeloid cells and elevated MDSC abundance proportional to tumor grade. Additionally, the tumors express substantial PD-L1 proportional to tumor grade. These results suggest a role for immune checkpoint inhibitors targeting the PD-L1/PD-1 pathway in combination with standard therapies for the treatment of high-grade meningiomas.
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Anticorpos Monoclonais/uso terapêutico , Antígeno B7-H1/antagonistas & inibidores , Terapia de Imunossupressão/métodos , Neoplasias Meníngeas/tratamento farmacológico , Meningioma/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais/imunologia , Antígeno B7-H1/imunologia , Feminino , Humanos , Estimativa de Kaplan-Meier , Linfócitos do Interstício Tumoral/efeitos dos fármacos , Linfócitos do Interstício Tumoral/imunologia , Linfócitos do Interstício Tumoral/metabolismo , Masculino , Neoplasias Meníngeas/imunologia , Neoplasias Meníngeas/patologia , Meningioma/imunologia , Meningioma/patologia , Pessoa de Meia-Idade , Células Supressoras Mieloides/efeitos dos fármacos , Células Supressoras Mieloides/imunologia , Células Supressoras Mieloides/metabolismo , Gradação de Tumores , Linfócitos T Reguladores/efeitos dos fármacos , Linfócitos T Reguladores/imunologia , Linfócitos T Reguladores/metabolismoRESUMO
BACKGROUND: Meningiomas are heterogeneous, with differences in anatomical, histopathological, and clinical characteristics. Such spatial variability in meningioma biology is thought to result from differences in the expression of critical developmental regulators. We hypothesized that the variability in meningioma biology would follow gradients such as in embryology and tested a cohort of 366 meningiomas for histopathological and immunohistochemical gradients. METHODS: The medical records from 366 patients treated for meningiomas from 2003 to 2016 were retrospectively analyzed for age, gender, anatomical localization, recurrence-free survival, overall survival, histopathological diagnosis, and immunohistochemistry findings for 6 markers: epithelial membrane antigen (EMA), progesterone receptor (PR), CD34, S100, p53, and Ki-67 labeling index. RESULTS: EMA, PR, S100, p53, and CD34 were expressed in 94%, 73%, 49%, 26%, and 23% of the tumors, respectively. p53 expression correlated positively with Ki-67 and World Health Organization (WHO) grade (rτ = 0.31 and rτ = 0.4, respectively). PR positivity correlated inversely with S100, p53, Ki-67, and WHO grade (rτ = -0.19, rτ = -0.14, rτ = -0.15, and rτ = -0.16, respectively). All secretory meningiomas were positive for EMA and PR and negative for S100, and this pattern exhibited a rostrocaudal gradient. The overall proportion of EMA+PR+S100- cases was significantly lower in the cranial vault (30.3%) than in the skull base (45.89%; P = 0.021). The proportion of WHO grade II-III tumors was greater in cranial vault than in skull base meningiomas. CONCLUSIONS: Unsupervised methods detected an association between the anatomical location and tumor biology in meningiomas. Unlike the categorical associations that former studies had indicated, the present study revealed a rostrocaudal gradient in both the cranial vault and the skull base, correlating with human developmental biology.