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Bhattacharya N, Rockstroh A, Deshpande SS, Thomas SK, Yadav A, Goswami C, Chawla S, Solomon P, Fourgeux C, Ahuja G, Hollier B, Kumar H, Roquilly A, Poschmann J, Lehman M, Nelson CC, Sengupta D. Artificial intelligence approaches for tumor phenotype stratification from single-cell transcriptomic data. eLife 2025; 13:RP98469. [PMID: 40511682 PMCID: PMC12165692 DOI: 10.7554/elife.98469] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/16/2025] Open
Abstract
Single-cell RNA-sequencing (scRNA-seq) coupled with robust computational analysis facilitates the characterization of phenotypic heterogeneity within tumors. Current scRNA-seq analysis pipelines are capable of identifying a myriad of malignant and non-malignant cell subtypes from single-cell profiling of tumors. However, given the extent of intra-tumoral heterogeneity, it is challenging to assess the risk associated with individual cell subpopulations, primarily due to the complexity of the cancer phenotype space and the lack of clinical annotations associated with tumor scRNA-seq studies. To this end, we introduce SCellBOW, a scRNA-seq analysis framework inspired by document embedding techniques from the domain of Natural Language Processing (NLP). SCellBOW is a novel computational approach that facilitates effective identification and high-quality visualization of single-cell subpopulations. We compared SCellBOW with existing best practice methods for its ability to precisely represent phenotypically divergent cell types across multiple scRNA-seq datasets, including our in-house generated human splenocyte and matched peripheral blood mononuclear cell (PBMC) dataset. For tumor cells, SCellBOW estimates the relative risk associated with each cluster and stratifies them based on their aggressiveness. This is achieved by simulating how the presence or absence of a specific cell subpopulation influences disease prognosis. Using SCellBOW, we identified a hitherto unknown and pervasive AR-/NElow (androgen-receptor-negative, neuroendocrine-low) malignant subpopulation in metastatic prostate cancer with conspicuously high aggressiveness. Overall, the risk-stratification capabilities of SCellBOW hold promise for formulating tailored therapeutic interventions by identifying clinically relevant tumor subpopulations and their impact on prognosis.
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Affiliation(s)
- Namrata Bhattacharya
- Australian Prostate Cancer Research Centre-Queensland, Faculty of Health, School of Biomedical Sciences, Centre for Genomics and Personalised Health, Queensland University of TechnologyBrisbaneAustralia
- Department of Computer Science and Engineering, Indraprastha Institute of Information Technology-Delhi (IIIT-Delhi), Okhla, Phase IIINew DelhiIndia
- Translational Research Institute, Princess Alexandra HospitalWoolloongabbaAustralia
| | - Anja Rockstroh
- Australian Prostate Cancer Research Centre-Queensland, Faculty of Health, School of Biomedical Sciences, Centre for Genomics and Personalised Health, Queensland University of TechnologyBrisbaneAustralia
- Translational Research Institute, Princess Alexandra HospitalWoolloongabbaAustralia
| | - Sanket Suhas Deshpande
- Department of Computational Biology, Indraprastha Institute of Information Technology-Delhi (IIIT-Delhi), Okhla, Phase IIINew DelhiIndia
| | - Sam Koshy Thomas
- School of Mathematical Sciences, The University of AdelaideAdelaideAustralia
| | - Anunay Yadav
- Department of Computer Science and Engineering, Indraprastha Institute of Information Technology-Delhi (IIIT-Delhi), Okhla, Phase IIINew DelhiIndia
| | - Chitrita Goswami
- Department of Computer Science and Engineering, Indraprastha Institute of Information Technology-Delhi (IIIT-Delhi), Okhla, Phase IIINew DelhiIndia
| | - Smriti Chawla
- Center for Computational Biomedicine, Harvard Medical SchoolBostonUnited States
| | - Pierre Solomon
- Nantes Université, CHU Nantes, INSERM, Center for Research in Transplantation and Translational Immunology, UMRNantesFrance
| | - Cynthia Fourgeux
- Nantes Université, CHU Nantes, INSERM, Center for Research in Transplantation and Translational Immunology, UMRNantesFrance
| | - Gaurav Ahuja
- Department of Computational Biology, Indraprastha Institute of Information Technology-Delhi (IIIT-Delhi), Okhla, Phase IIINew DelhiIndia
- Centre for Artificial Intelligence, Indraprastha Institute of Information Technology-Delhi (IIIT-Delhi), Okhla, Phase IIINew DelhiIndia
| | - Brett Hollier
- Australian Prostate Cancer Research Centre-Queensland, Faculty of Health, School of Biomedical Sciences, Centre for Genomics and Personalised Health, Queensland University of TechnologyBrisbaneAustralia
- Translational Research Institute, Princess Alexandra HospitalWoolloongabbaAustralia
| | - Himanshu Kumar
- Laboratory of Immunology and Infectious Disease Biology, Department of Biological Sciences, Indian Institute of Science Education and Research (IISER)BhopalIndia
| | - Antoine Roquilly
- Nantes Université, CHU Nantes, INSERM, Center for Research in Transplantation and Translational Immunology, UMRNantesFrance
| | - Jeremie Poschmann
- Nantes Université, CHU Nantes, INSERM, Center for Research in Transplantation and Translational Immunology, UMRNantesFrance
| | - Melanie Lehman
- Australian Prostate Cancer Research Centre-Queensland, Faculty of Health, School of Biomedical Sciences, Centre for Genomics and Personalised Health, Queensland University of TechnologyBrisbaneAustralia
- Vancouver Prostate Centre, Department of Urologic Sciences, University of British ColumbiaVancouverCanada
| | - Colleen C Nelson
- Australian Prostate Cancer Research Centre-Queensland, Faculty of Health, School of Biomedical Sciences, Centre for Genomics and Personalised Health, Queensland University of TechnologyBrisbaneAustralia
- Translational Research Institute, Princess Alexandra HospitalWoolloongabbaAustralia
| | - Debarka Sengupta
- Department of Computer Science and Engineering, Indraprastha Institute of Information Technology-Delhi (IIIT-Delhi), Okhla, Phase IIINew DelhiIndia
- Department of Computational Biology, Indraprastha Institute of Information Technology-Delhi (IIIT-Delhi), Okhla, Phase IIINew DelhiIndia
- Centre for Artificial Intelligence, Indraprastha Institute of Information Technology-Delhi (IIIT-Delhi), Okhla, Phase IIINew DelhiIndia
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Lee GA, Hsu JBK, Chang YW, Hsieh LC, Li YT, Wu YC, Chu CY, Chiang YH, Guo WY, Wu CC, Chen LW, Kao HW, Lin WL, Tseng LW, Weng TW, Kuo DP, Cheng SJ, Chen YC, Huang SW, Kung HJ, Chen CY. IL-19 as a promising theranostic target to reprogram the glioblastoma immunosuppressive microenvironment. J Biomed Sci 2025; 32:34. [PMID: 40057744 PMCID: PMC11889942 DOI: 10.1186/s12929-025-01126-w] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2024] [Accepted: 02/13/2025] [Indexed: 04/30/2025] Open
Abstract
BACKGROUND Glioblastoma multiforme (GBM) is an aggressive brain tumor with chemoresistant, immunosuppressive, and invasive properties. Despite standard therapies, including surgery, radiotherapy, and temozolomide (TMZ) chemotherapy, tumors inevitably recur in the peritumoral region. Targeting GBM-mediated immunosuppressive and invasive properties is a promising strategy to improve clinical outcomes. METHODS We utilized clinical and genomic data from the Taiwan GBM cohort and The Cancer Genome Atlas (TCGA) to analyze RNA sequencing data from patient tumor samples, determining the association of interleukin-19 (Il-19) expression with survival and immunosuppressive activity. Gene set enrichment analysis (GSEA) was performed to assess the relationship between the enrichment levels of immune subsets and Il-19 expression level, and Ingenuity Pathway Analysis (IPA) was used to predict immune responses. Cytokine array and single-cell RNA sequencing were used to examine the effects of IL-19 blockade on tumor immune microenvironment, including tumor-infiltrating leukocyte profiles, differentiation and immunosuppressive genes expression in tumor associated macrophages (TAM). CRISPR Il-19-/- cell lines and Il-19-/- mice were used to examine the role of IL-19 in tumor invasion and M2-like macrophage-mediated immunosuppression. Additionally, we developed novel cholesterol-polyethylene glycol-superparamagnetic iron oxide-IL-19 antibody nanoparticles (CHOL-PEG-SPIO-IL-19), characterized them using dynamic light scattering and transmission electron microscopy, Fourier-Transform Infrared spectroscopy, prussian blue assay, and conducted in vivo magnetic resonance imaging (MRI) in a human glioblastoma stem cell-derived GBM animal model. RESULT Genomic screening and IPA analysis identified IL-19 as a predicted immunosuppressive cytokine in the peritumoral region, associated with poor survival in patients with GBM. Blocking IL-19 significantly inhibited tumor progression of both TMZ-sensitive (TMZ-S) and TMZ-resistant (TMZ-R) GBM-bearing mice, and modulated the immune response within the GBM microenvironment. Single-cell transcriptome analysis reveal that IL-19 antibody treatment led to a marked increase in dendritic cells and monocyte/macrophage subsets associated with interferon-gamma signaling pathways. IL-19 blockade promoted T cell activation and reprogrammed tumor-associated macrophages toward weakened pro-tumoral phenotypes with reduced Arginase 1 expression. Il19-/- M2-like bone marrow-derived macrophages with lower Arginase 1 level lost their ability to suppress CD8 T cell activation. These findings indicated that IL-19 suppression limits TAM-mediated immune suppression. Molecular studies revealed that IL-19 promotes TMZ-resistant GBM cell migration and invasion through a novel IL-19/WISP1 signaling pathway. For clinical translation, we developed a novel CHOL-PEG-SPIO-IL-19 nanoparticles to target IL-19 expression in glioblastoma tissue. MRI imaging demonstrated enhanced targeting efficiency in brain tumors, with in vivo studies showing prominent hypointense areas in T2*-weighted MRI scans of tumor-bearing mice injected with CHOL-PEG-SPIO-IL-19, highlighting nanoparticle presence in IL-19-expressing regions. Prussian blue staining further confirmed the localization of these nanoparticles in tumor tissues, verifying their potential as a diagnostic tool for detecting IL-19 expression in glioblastoma. This system offers a theranostic approach, integrating diagnostic imaging and targeted therapy for IL-19-expressing GBM. CONCLUSION IL-19 is a promising theranostic target for reversing immunosuppression and restricting the invasive activity of chemoresistant GBM cells.
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Affiliation(s)
- Gilbert Aaron Lee
- Department of Medical Research, Taipei Medical University Hospital, Taipei, Taiwan.
- Department of Microbiology and Immunology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan.
- Child Development Research Center, Taipei Medical University Hospital, No. 250, Wu Hsing Street, Taipei, 110, Taiwan.
- TMU Research Center for Digestive Medicine, Taipei Medical University, Taipei, Taiwan.
| | - Justin Bo-Kai Hsu
- Department of Computer Science and Engineering, Yuan Ze University, Taoyuan, Taiwan
| | - Yu-Wei Chang
- Department of Medical Research, Taipei Medical University Hospital, Taipei, Taiwan
| | - Li-Chun Hsieh
- Department of Radiology, School of Medicine, College of Medicine, Taipei Medical University, No. 250, Wu Hsing Street, Taipei, 110, Taiwan
- Department of Medical Imaging, Taipei Medical University Hospital, Taipei, Taiwan
| | - Yi-Tien Li
- Translational Imaging Research Center, Taipei Medical University Hospital, Taipei, Taiwan
- Neuroscience Research Center, Taipei Medical University, Taipei, Taiwan
- Ph.D. Program in Medical Neuroscience, College of Medical Science and Technology, Taipei Medical University, Taipei, 11031, Taiwan
| | - Ying Chieh Wu
- Department of Medical Research, Taipei Medical University Hospital, Taipei, Taiwan
| | - Cheng-Ying Chu
- CRISPR Gene Targeting Core, Taipei Medical University, Taipei 110, Taiwan
- TMU Research Center of Cancer Translational Medicine, Taipei Medical University, Taipei 110, Taiwan
| | - Yung-Hsiao Chiang
- Department of Surgery, College of Medicine, Taipei Medical University, Taipei, Taiwan
| | - Wan-Yuo Guo
- Department of Radiology, Taipei Veterans General Hospital, Taipei, Taiwan
| | - Chih-Chun Wu
- Department of Radiology, Taipei Veterans General Hospital, Taipei, Taiwan
| | - Liang-Wei Chen
- Department of Radiology, Taipei Veterans General Hospital, Taipei, Taiwan
| | - Hung-Wen Kao
- Radiological Diagnosis Department, Tri-Service General Hospital, Taipei, Taiwan
| | - Wan-Li Lin
- Department of Nuclear Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan
| | - Li-Wen Tseng
- Department of Medical Research, Taipei Medical University Hospital, Taipei, Taiwan
| | - Ting-Wei Weng
- Department of Medical Research, Taipei Medical University Hospital, Taipei, Taiwan
| | - Duen-Pang Kuo
- Department of Radiology, School of Medicine, College of Medicine, Taipei Medical University, No. 250, Wu Hsing Street, Taipei, 110, Taiwan
| | - Sho-Jen Cheng
- Department of Medical Imaging, Taipei Medical University Hospital, Taipei, Taiwan
| | - Yung-Chieh Chen
- Department of Medical Imaging, Taipei Medical University Hospital, Taipei, Taiwan
| | - Shiu-Wen Huang
- Department of Pharmacology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan
- Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei, Taiwan
| | - Hsing-Jien Kung
- Research Center of Cancer Translational Medicine, Taipei Medical University, Taipei, Taiwan
| | - Cheng-Yu Chen
- Department of Radiology, School of Medicine, College of Medicine, Taipei Medical University, No. 250, Wu Hsing Street, Taipei, 110, Taiwan.
- Department of Medical Imaging, Taipei Medical University Hospital, Taipei, Taiwan.
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Grimes JM, Ghosh S, Manzoor S, Li LX, Moran MM, Clements JC, Alexander SD, Markert JM, Leavenworth JW. Oncolytic reprogramming of tumor microenvironment shapes CD4 T-cell memory via the IL6ra-Bcl6 axis for targeted control of glioblastoma. Nat Commun 2025; 16:1095. [PMID: 39885128 PMCID: PMC11782536 DOI: 10.1038/s41467-024-55455-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2024] [Accepted: 12/13/2024] [Indexed: 02/01/2025] Open
Abstract
Oncolytic viruses (OVs) emerge as a promising cancer immunotherapy. However, the temporal impact on tumor cells and the tumor microenvironment, and the nature of anti-tumor immunity post-therapy remain largely unclear. Here we report that CD4+ T cells are required for durable tumor control in syngeneic murine models of glioblastoma multiforme after treatment with an oncolytic herpes simplex virus (oHSV) engineered to express IL-12. The upregulated MHCII on residual tumor cells facilitates programmed polyfunctional CD4+ T cells for tumor control and for recall responses. Mechanistically, the proper ratio of Bcl-6 to T-bet in CD4+ T cells navigates their enhanced anti-tumor capacity, and a reciprocal IL6ra-Bcl-6 regulatory axis in a memory CD4+ T-cell subset, which requires MHCII signals from reprogrammed tumor cells, tumor-infiltrating and resident myeloid cells, is necessary for the prolonged response. These findings uncover an OV-induced tumor/myeloid-CD4+ T-cell partnership, leading to long-term anti-tumor immune memory, and improved OV therapeutic efficacy.
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Affiliation(s)
- Jeffrey M Grimes
- Department of Neurosurgery, University of Alabama at Birmingham, Birmingham, AL, USA
- Graduate Biomedical Sciences Program, University of Alabama at Birmingham, Birmingham, AL, USA
| | - Sadashib Ghosh
- Department of Neurosurgery, University of Alabama at Birmingham, Birmingham, AL, USA
| | - Shamza Manzoor
- Department of Neurosurgery, University of Alabama at Birmingham, Birmingham, AL, USA
| | - Li X Li
- Department of Neurosurgery, University of Alabama at Birmingham, Birmingham, AL, USA
| | - Monica M Moran
- Department of Neurosurgery, University of Alabama at Birmingham, Birmingham, AL, USA
- Graduate Biomedical Sciences Program, University of Alabama at Birmingham, Birmingham, AL, USA
| | - Jennifer C Clements
- Department of Neurosurgery, University of Alabama at Birmingham, Birmingham, AL, USA
| | - Sherrie D Alexander
- Department of Neurosurgery, University of Alabama at Birmingham, Birmingham, AL, USA
| | - James M Markert
- Department of Neurosurgery, University of Alabama at Birmingham, Birmingham, AL, USA
- The O'Neal Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, AL, USA
| | - Jianmei W Leavenworth
- Department of Neurosurgery, University of Alabama at Birmingham, Birmingham, AL, USA.
- The O'Neal Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, AL, USA.
- Department of Microbiology, University of Alabama at Birmingham, Birmingham, AL, USA.
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de Melo SM, Elias Nunes da Silva ME, Torloni MR, Riera R, De Cicco K, Latorraca CO, Pinto ACPN. Anti-PD-1 and anti-PD-L1 antibodies for glioma. Cochrane Database Syst Rev 2025; 1:CD012532. [PMID: 39777725 PMCID: PMC11707826 DOI: 10.1002/14651858.cd012532.pub2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/11/2025]
Abstract
BACKGROUND Glioblastoma multiforme (GBM) is the most common and aggressive adult glioma (16-month median survival). Its immunosuppressive microenvironment limits the efficacy of immune checkpoint inhibitors (ICIs). OBJECTIVES To assess the effects of the ICIs antibodies anti-programmed cell death 1 (anti-PD-1) and anti-programmed cell death ligand 1 (anti-PD-L1) in treating adults with diffuse glioma. SEARCH METHODS We searched CENTRAL, MEDLINE, Embase, and clinical trials registers on 8 March 2024. SELECTION CRITERIA We included randomised controlled trials (RCTs) evaluating adults with diffuse glioma treated with anti-PD-1/PD-L1 compared to placebo or other therapies used alone or with other ICIs. Primary outcomes were overall survival (OS), progression-free survival (PFS), and serious adverse events (SAE). Secondary outcomes were overall response rate (ORR), quality of life (QoL), and less serious AEs. DATA COLLECTION AND ANALYSIS We followed standard Cochrane methods. MAIN RESULTS We included seven RCTs evaluating anti-PD-1 treatment in recurrent (N = 4) and newly diagnosed (N = 3) grade 4 glioma participants. The analysis encompassed 1953 participants; sample sizes ranged from 35 to 716. Meta-analyses were not possible due to heterogeneity and the small number of studies. Most trials had high risk of bias. Nivolumab versus bevacizumab in people with recurrent GBM (1 trial, 369 participants) Nivolumab probably does not increase OS (hazard ratio (HR) 1.04, 95% confidence interval (CI) 0.83 to 1.30; 1.3% more, 95% CI 6.30 fewer to 7.80 more; 369 participants; moderate-certainty evidence) or PFS (HR 1.97, 95% CI 1.57 to 2.48; 16.40% more, 95% CI 12.40 more to 19.00 more; 369 participants; moderate-certainty evidence). The evidence for SAE is very uncertain (risk ratio (RR) 1.20, 95% CI 0.74 to 1.92; 347 participants). Nivolumab probably does not increase ORR (RR 0.34, 95% CI 0.18 to 0.63; 309 participants; moderate-certainty evidence), but may not increase less serious AEs (RR 1.03, 95% CI 0.96 to 1.10; 347 participants; low-certainty evidence). Nivolumab plus bevacizumab 10 mg/kg versus nivolumab plus bevacizumab 3 mg/kg in people with recurrent GBM (1 trial, 90 participants) Nivolumab plus bevacizumab 10 mg/kg may not increase OS (HR 1.39, 95% CI 0.86 to 2.25; 9.90% more, 95% CI 5.20 fewer to 18.80 more; 90 participants; low-certainty evidence). The evidence for PFS (HR 1.23, 95% CI 0.78 to 1.93; 5.80% more, 95% CI 8.20 fewer to 14.20 more; 90 participants) and SAE (RR 1.19, 95% CI 0.79 to 1.79; 90 participants) is very uncertain. Nivolumab may not increase less serious AEs (RR 1.02, 95% CI 0.96 to 1.09; low-certainty evidence; 90 participants). Pembrolizumab plus bevacizumab versus pembrolizumab in people with recurrent GBM (1 trial, 80 participants) The evidence for OS (HR 1.03, 95% CI 0.65 to 1.63; 0.30% more, 95% CI 7.60 fewer to 2.90 more; 80 participants), PFS (HR 0.97, 95% CI 0.61 to 1.54: 0.40% fewer, 95% CI 9.20 fewer to 2.80 more; 80 participants), SAE (RR 1.32, 95% CI 0.75 to 2.42; 80 participants), and ORR (RR 12.76, 95% CI 0.77 to 210.27; 80 participants) is very uncertain. Pembrolizumab plus bevacizumab may not increase less serious AEs (RR 1.04, 95% CI 0.96 to 1.13; 80 participants; low-certainty evidence). Neoadjuvant (before surgical resection) and adjuvant (after surgical resection) pembrolizumab versus adjuvant-only pembrolizumab in people with recurrent GBM (1 trial, 35 participants) The evidence for OS (HR 0.39, 95% CI 0.17 to 0.92; 25.20% fewer, 95% CI 37.10 fewer to 2.10 fewer; 35 participants), PFS (HR 0.43, 95% CI 0.20 to 0.91; 30.10% fewer, 95% CI 52.20 fewer to 3.60 fewer; 35 participants), and SAE (RR 1.00, 95% CI 0.31 to 3.28; 32 participants) is very uncertain. Nivolumab plus radiotherapy versus temozolomide plus radiotherapy in people with newly diagnosed unmethylated GBM (1 trial, 560 participants) Nivolumab plus radiotherapy probably does not increase OS (HR 1.31, 95% CI 1.09 to 1.58 months; 8.30% more, 95% CI 2.80 more to 12.90 more; 560 participants) and PFS (HR 1.38, 95% CI 1.15 to 1.65 months; 7.50% more, 95% CI 3.60 more to 10.30 more; 560 participants; moderate-certainty evidence). The evidence for SAE is very uncertain (RR 0.87, 95% CI 0.65 to 1.18; 553 participants). It may not increase ORR (RR 1.08, 95% CI 0.43 to 2.69; 560 participants; low-certainty evidence) and probably does not increase less serious AEs (RR 1.00, 95% CI 0.96 to 1.04; 560 participants; moderate-certainty evidence). The evidence for time to deterioration of QoL is very uncertain (HR 0.76, 95% CI 0.59 to 0.99; 560 participants). Nivolumab plus temozolomide plus radiotherapy versus placebo plus temozolomide plus radiotherapy in people with newly diagnosed methylated GBM (1 trial, 716 participants) Nivolumab plus temozolomide plus radiotherapy probably does not increase OS (HR 1.10, 95% CI 0.92 to 1.32; 3.50 more, 95% CI 3.80 fewer to 9.60 more; 716 participants) and PFS (HR 1.10, 95% CI 0.92 to 1.32; 3.00 more, 95% CI 3.50 fewer to 7.90 more; 716 participants), and probably increases SAE (RR 2.91, 95% CI 2.05 to 4.12; 709 participants; moderate-certainty evidence). It does not increase less serious AEs (RR 1.02, 95% CI 1.00 to 1.04; 709 participants; high-certainty evidence). Adjuvant nivolumab plus temozolomide versus temozolomide in older people with GBM (1 trial, 103 participants) Nivolumab plus temozolomide probably does not increase OS (HR 0.85, 95% CI 0.54 to 1.33; 3.10 fewer, 95% CI 15.80 fewer to 3.60 more; 103 participants; moderate-certainty evidence) and PFS (HR 0.77, 95% CI 0.49 to 1.19; 5.40 fewer, 95% CI 19.10 fewer to 2.40 more; 103 participants; moderate-certainty evidence). The evidence for SAE is very uncertain (RR 1.58, 95% CI 0.88 to 2.81; 103 participants). The evidence for QoL is very uncertain (results only reported graphically; 103 participants). AUTHORS' CONCLUSIONS In recurrent GBM, nivolumab alone probably has no benefit. Anti-PD1 plus bevacizumab may also be ineffective based on low- to very low-certainty evidence. Neoadjuvant plus adjuvant pembrolizumab may improve OS and PFS, but this was based on only one small trial and very low-certainty evidence. In newly diagnosed GBM, nivolumab plus radiotherapy in unmethylated and plus radiotherapy plus temozolomide in methylated GBM probably has no benefit. In older participants, adjuvant nivolumab probably offers no benefit.
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Affiliation(s)
- Suely M de Melo
- Departamento de Neurocirurgia, Escola Paulista de Medicina (EPM), Universidade Federal de Sao Paulo (UNIFESP), São Paulo, Brazil
- Neuro Oncologia, Hospital do Coração de São Paulo, São Paulo, Brazil
- Saúde Baseada em Evidências, Escola Paulista de Medicina, Universidade Federal de São Paulo, São Paulo, Brazil
| | | | | | - Rachel Riera
- Núcleo de Ensino e Pesquisa em Saúde Baseada em Evidências e Avaliação Tecnológica em Saúde (NEP-Sbeats) , Universidade Federal de São Paulo, São Paulo, Brazil
- Cochrane Afilliate Rio de Janeiro, Petrópolis, Brazil
- Center of Health Technology Assessment, Hospital Sírio-Libanês, São Paulo, Brazil
| | | | | | - Ana Carolina Pereira Nunes Pinto
- Saúde Baseada em Evidências, Escola Paulista de Medicina, Universidade Federal de São Paulo, São Paulo, Brazil
- Cochrane Brazil, São Paulo, Brazil
- Iberoamerican Cochrane Centre - Biomedical Research Institute Sant Pau (IIB Sant Pau), Barcelona, Spain
- Departamento de Ciências Biológicas e da Saúde, Universidade Federal do Amapá, Macapá, Brazil
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Brem S. Vagus nerve stimulation: Novel concept for the treatment of glioblastoma and solid cancers by cytokine (interleukin-6) reduction, attenuating the SASP, enhancing tumor immunity. Brain Behav Immun Health 2024; 42:100859. [PMID: 39512605 PMCID: PMC11541944 DOI: 10.1016/j.bbih.2024.100859] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2024] [Revised: 07/31/2024] [Accepted: 09/07/2024] [Indexed: 11/15/2024] Open
Abstract
Immuno-oncology, specifically immune checkpoint inhibitors (ICIs), has revolutionized cancer care with dramatic, long-term responses and increased survival, including patients with metastatic cancer to the brain. Glioblastomas, and other primary brain tumors, are refractory to ICIs as monotherapy or in combination with standard therapy. The tumor microenvironment (TME) poses multiple biological hurdles: blood-brain barrier, immune suppression, heterogeneity, and tumor infiltration. Genomic analysis of the senescence-associated secretory phenotype (SASP) and preclinical models of glioma suggest that an exciting approach would entail reprogramming of the glioma microenvironment, attenuating the pro-inflammatory, pro-tumorigenic cytokines of the SASP, especially interleukin-6 (IL-6). A testable hypothesis now proposed is to modulate the immune system by harnessing the body's 'inflammatory reflex' to reduce cytokines. Vagus nerve stimulation can activate T cell immunity by the cholinergic, α7nicotinic acetylcholine receptor agonist (α7nAchR), and suppress IL-6 systemically, as well as other pro-inflammatory cytokines of the SASP, interleukin -1β (IL-1β) and tumor necrosis factor-alpha (TNF-α). The hypothesis predicts that electrical activation of the vagus nerve, with cytokine reduction, in combination with ICIs, would convert an immune resistant ("cold") tumor to an immune responsive ("hot") tumor, and halt glioma progression. The hypothesis also envisions cancer as an immune "dysautonomia" whereby a therapeutic intervention, vagus nerve stimulation (VNS), resets the systemic and local cytokine levels. A prospective, randomized, phase II clinical trial, to confirm the hypothesis, is a logical, exigent, next step. Cytokine reduction by VNS could also be useful for other forms of human cancer, e.g., breast, colorectal, head and neck, lung, melanoma, ovarian, pancreatic, and prostate cancer, as the emerging field of "cancer neuroscience" shows a role for neural regulation of multiple tumor types. Because IL-6, and companion pro-inflammatory cytokines, participate in the initiation, progression, spread and recurrence of cancer, minimally invasive VNS could be employed to suppress glioma or cancer progression, while also mitigating depression and/or seizures, thereby enhancing quality of life. The current hypothesis reimagines glioma pathophysiology as a dysautonomia with the therapeutic objective to reset the autonomic nervous system and form an immune responsive state to halt tumor progression and prevent recurrence. VNS, as a novel method to control cancer, can be administered with ICIs, standard therapy, or in clinical trials, combined with emerging immunotherapy: dendritic cell, mRNA, or chimeric antigen receptor (CAR) T cell vaccines.
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Affiliation(s)
- Steven Brem
- University of Pennsylvania, Department of Neurosurgery, Perelman Center for Advanced Medicine, 15-141, 3400 Civic Center Blvd., Philadelphia, PA, 19104, United States
- Glioblastoma Translational Center of Excellence, Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA, 19104, United States
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Ivanov SM, Lagunin AA, Tarasova OA. Analysis of transcription profiles for the identification of master regulators as the key players in glioblastoma. Comput Struct Biotechnol J 2024; 23:3559-3574. [PMID: 39963421 PMCID: PMC11832006 DOI: 10.1016/j.csbj.2024.09.022] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2024] [Revised: 09/23/2024] [Accepted: 09/26/2024] [Indexed: 02/20/2025] Open
Abstract
Glioblastoma (GBM) is the most common malignant brain tumor with poor overall survival. Current treatment management for GBM has low efficacy, mainly due to high inter-patient heterogeneity. The transcription profiles in GBM define cell properties essential for tumor progression. We have developed an approach for the identification of master regulators (MRs) that are responsible for the gene expression changes in GBM. The approach is based on transcription factor enrichment analysis with subsequent "upstream" analysis in the signaling network. The main feature of the approach is that all calculations are performed for transcription profiles from individual samples, which allows taking into account GBM transcription heterogeneity. We identified 451 MRs that were up-regulated or down-regulated and, thus, were important parts of positive feedback loops. The number of MRs in the samples correlated with the degree of tumor immune infiltration, while the differences in MR profiles were generally consistent with the known GBM subtypes: mesenchymal, classical, and proneural. MRs densely interact with each other in the signaling network that may be associated with the robustness to pharmacological intervention. We identified 102 receptors among MRs, which is coherent with the importance of cell-cell interactions for GBM progression. The role of some of them in GBM is not currently investigated: lysophosphatidic acid receptors 5 and 6, sphingosine-1-phosphate receptor 4, lysophosphatidylserine receptors GPR34 and GPR174, and G protein-coupled receptors 84 and 132 for fatty acids. Information on the revealed MRs can be used to search for novel therapeutic strategies to treat GBM.
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Affiliation(s)
- Sergey M. Ivanov
- Department of Bioinformatics, Institute of Biomedical Chemistry, Pogodinskaya Street, 10 bldg. 8, Moscow 119121, Russia
- Department of Bioinformatics, Pirogov Russian National Research Medical University, Ostrovityanova Street, 1, Moscow 117997, Russia
| | - Alexey A. Lagunin
- Department of Bioinformatics, Institute of Biomedical Chemistry, Pogodinskaya Street, 10 bldg. 8, Moscow 119121, Russia
- Department of Bioinformatics, Pirogov Russian National Research Medical University, Ostrovityanova Street, 1, Moscow 117997, Russia
| | - Olga A. Tarasova
- Department of Bioinformatics, Institute of Biomedical Chemistry, Pogodinskaya Street, 10 bldg. 8, Moscow 119121, Russia
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7
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Norollahi SE, Yousefi B, Nejatifar F, Yousefzadeh-Chabok S, Rashidy-Pour A, Samadani AA. Practical immunomodulatory landscape of glioblastoma multiforme (GBM) therapy. J Egypt Natl Canc Inst 2024; 36:33. [PMID: 39465481 DOI: 10.1186/s43046-024-00240-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2024] [Accepted: 09/21/2024] [Indexed: 10/29/2024] Open
Abstract
Glioblastoma multiforme (GBM) is the most common harmful high-grade brain tumor with high mortality and low survival rate. Importantly, besides routine diagnostic and therapeutic methods, modern and useful practical techniques are urgently needed for this serious malignancy. Correspondingly, the translational medicine focusing on genetic and epigenetic profiles of glioblastoma, as well as the immune framework and brain microenvironment, based on these challenging findings, indicates that key clinical interventions include immunotherapy, such as immunoassay, oncolytic viral therapy, and chimeric antigen receptor T (CAR T) cell therapy, which are of great importance in both diagnosis and therapy. Relatively, vaccine therapy reflects the untapped confidence to enhance GBM outcomes. Ongoing advances in immunotherapy, which utilizes different methods to regenerate or modify the resistant body for cancer therapy, have revealed serious results with many different problems and difficulties for patients. Safe checkpoint inhibitors, adoptive cellular treatment, cellular and peptide antibodies, and other innovations give researchers an endless cluster of instruments to plan profoundly in personalized medicine and the potential for combination techniques. In this way, antibodies that block immune checkpoints, particularly those that target the program death 1 (PD-1)/PD-1 (PD-L1) ligand pathway, have improved prognosis in a wide range of diseases. However, its use in combination with chemotherapy, radiation therapy, or monotherapy is ineffective in treating GBM. The purpose of this review is to provide an up-to-date overview of the translational elements concentrating on the immunotherapeutic field of GBM alongside describing the molecular mechanism involved in GBM and related signaling pathways, presenting both historical perspectives and future directions underlying basic and clinical practice.
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Affiliation(s)
- Seyedeh Elham Norollahi
- Cancer Research Center and, Department of Immunology, Semnan University of Medical Sciences, Semnan, Iran
| | - Bahman Yousefi
- Cancer Research Center and, Department of Immunology, Semnan University of Medical Sciences, Semnan, Iran
| | - Fatemeh Nejatifar
- Department of Hematology and Oncology, School of Medicine, Razi Hospital, Guilan University of Medical Sciences, Rasht, Iran
| | - Shahrokh Yousefzadeh-Chabok
- Guilan Road Trauma Research Center, Trauma Institute, Guilan University of Medical Sciences, Rasht, Iran
- , Rasht, Iran
| | - Ali Rashidy-Pour
- Research Center of Physiology, Semnan University of Medical Sciences, Semnan, Iran.
| | - Ali Akbar Samadani
- Guilan Road Trauma Research Center, Trauma Institute, Guilan University of Medical Sciences, Rasht, Iran.
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8
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Xiong J, Zhou X, Su L, Jiang L, Ming Z, Pang C, Fuller C, Xu K, Chi H, Zheng X. The two-sided battlefield of tumour-associated macrophages in glioblastoma: unravelling their therapeutic potential. Discov Oncol 2024; 15:590. [PMID: 39453528 PMCID: PMC11511804 DOI: 10.1007/s12672-024-01464-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/09/2024] [Accepted: 10/15/2024] [Indexed: 10/26/2024] Open
Abstract
Gliomas are the most common primary malignant tumours of the central nervous system (CNS), which are highly aggressive, with increasing morbidity and mortality rates year after year, posing a serious threat to the quality and expected survival time of patients. The treatment of gliomas is a major challenge in the field of neuro-oncology, especially high-grade gliomas such as glioblastomas (GBMs). Despite considerable progress in recent years in the study of the molecular and cellular mechanisms of GBMs, their prognosis remains bleak. Tumour-associated macrophages (TAMs) account for up to 50% of GBMs, and they are a highly heterogeneous cell population whose role cannot be ignored. Here, we focus on reviewing the contribution of classically activated M1-phenotype TAMs and alternatively activated M2-phenotype TAMs to GBMs, and exploring the research progress in reprogramming M1 TAMs into M2 TAMs.
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Affiliation(s)
- Jingwen Xiong
- Department of Sports Rehabilitation, Affiliated Hospital of Southwest Medical University, Luzhou, 646000, China
| | - Xuancheng Zhou
- Clinical Medical College, Affiliated Hospital of Southwest Medical University, Luzhou, 646000, China
| | - Lanqian Su
- Clinical Medical College, Affiliated Hospital of Southwest Medical University, Luzhou, 646000, China
| | - Lai Jiang
- Clinical Medical College, Affiliated Hospital of Southwest Medical University, Luzhou, 646000, China
| | - Ziwei Ming
- Department of Sports Rehabilitation, Affiliated Hospital of Southwest Medical University, Luzhou, 646000, China
| | - Can Pang
- School of Public Health, Lanzhou University, Lanzhou, 730000, China
| | - Claire Fuller
- Whiting School of Engineering, Johns Hopkins University, Baltimore, MD, 21224, USA
| | - Ke Xu
- Department of Oncology, Chongqing General Hospital, Chongqing University, Chongqing, 401147, China.
| | - Hao Chi
- Clinical Medical College, Affiliated Hospital of Southwest Medical University, Luzhou, 646000, China.
| | - Xiaomei Zheng
- Department of Neurology, Affiliated Hospital of Southwest Medical University, Luzhou, 646000, China.
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9
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Yan RE, Greenfield JP. Challenges and Outlooks in Precision Medicine: Expectations Versus Reality. World Neurosurg 2024; 190:573-581. [PMID: 39425299 DOI: 10.1016/j.wneu.2024.06.142] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2024] [Accepted: 06/25/2024] [Indexed: 10/21/2024]
Abstract
Recent developments in technology have led to rapid advances in precision medicine, especially due to the rise of next-generation sequencing and molecular profiling. These technological advances have led to rapid advances in research, including increased tumor subtype resolution, new therapeutic agents, and mechanistic insights. Certain therapies have even been approved for molecular biomarkers across histopathological diagnoses; however, translation of research findings to the clinic still faces a number of challenges. In this review, the authors discuss several key challenges to the clinical integration of precision medicine, including the blood-brain barrier, both a lack and excess of molecular targets, and tumor heterogeneity/escape from therapy. They also highlight a few key efforts to address these challenges, including new frontiers in drug delivery, a rapidly expanding treatment repertoire, and improvements in active response monitoring. With continued improvements and developments, the authors anticipate that precision medicine will increasingly become the gold standard for clinical care.
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Affiliation(s)
- Rachel E Yan
- Department of Neurological Surgery, Weill Cornell Medicine, New York, New York, USA
| | - Jeffrey P Greenfield
- Department of Neurological Surgery, NewYork-Presbyterian Weill Cornell Medicine, New York, New York, USA.
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10
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Batara DC, Kim HJ, Phan LT, Kim M, Son YO, Lee S, Park SI, Choi YS, Beck S, Kim SH. Elevated α-1,2-mannosidase MAN1C1 in glioma stem cells and its implications for immunological changes and prognosis in glioma patients. Sci Rep 2024; 14:22159. [PMID: 39333557 PMCID: PMC11436702 DOI: 10.1038/s41598-024-72901-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2024] [Accepted: 09/11/2024] [Indexed: 09/29/2024] Open
Abstract
Glioblastoma multiforme (GBM) is the most aggressive type of primary brain tumor, and the presence of glioma stem cells (GSCs) has been linked to its resistance to treatments and recurrence. Additionally, aberrant glycosylation has been implicated in the aggressiveness of cancers. However, the influence and underlying mechanism of N-glycosylation on the GSC phenotype and GBM malignancy remain elusive. Here, we performed an in-silico analysis approach on publicly available datasets to examine the function of N-glycosylation-related genes in GSCs and gliomas, accompanied by a qRT-PCR validation experiment. We found that high α-1,2-mannosidase MAN1C1 is associated with immunological functions and worse survival of glioma patients. Differential gene expression analysis and qRT-PCR validation revealed that MAN1C1 is highly expressed in GSCs. Furthermore, higher MAN1C1 expression predicts worse outcomes in glioma patients. Also, MAN1C1 expression is increased in the perinecrotic region of GBM and is associated with immunological and inflammatory functions, a hallmark of the GBM mesenchymal subtype. Further analysis confirmed that MAN1C1 expression is closely associated with infiltrating immune cells and disrupted immune response in the GBM microenvironment. These suggest that MAN1C1 is a potential biomarker for gliomas and may be important as an immunotherapeutic target for GBM.
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Affiliation(s)
- Don Carlo Batara
- Animal Molecular Biochemistry Laboratory, Department of Animal Science, College of Agriculture and Life Sciences, Chonnam National University, Gwangju, 61186, Republic of Korea
| | - Hyun-Jin Kim
- Animal Molecular Biochemistry Laboratory, Department of Animal Science, College of Agriculture and Life Sciences, Chonnam National University, Gwangju, 61186, Republic of Korea
| | - Le Thi Phan
- Animal Molecular Biochemistry Laboratory, Department of Animal Science, College of Agriculture and Life Sciences, Chonnam National University, Gwangju, 61186, Republic of Korea
- Computational Biology and Bioinformatics Laboratory, Department of Integrative Biotechnology, Sungkyunkwan University, Suwon, Gyeonggi-do, 16419, Republic of Korea
| | - Minseo Kim
- Animal Molecular Biochemistry Laboratory, Department of Animal Science, College of Agriculture and Life Sciences, Chonnam National University, Gwangju, 61186, Republic of Korea
| | - Young-Ok Son
- Department of Animal Biotechnology, Faculty of Biotechnology, College of Applied Life Sciences, Interdisciplinary Graduate Program in Advanced Convergence Technology and Science, Jeju National University, Jeju, 63243, Republic of Korea
| | - Seongsoo Lee
- Gwangju Center, Korea Basic Science Institute (KBSI), 49, Dosicheomdansaneop-ro, Nam-gu, Gwangju, 61751, Republic of Korea
- Department of Systems Biotechnology, Chung-Ang University, Anseong-si, Gyeonggi-do, 17546, Republic of Korea
| | - Sang-Ik Park
- Laboratory of Veterinary Pathology, College of Veterinary Medicine and BK21 Plus Project Team, Chonnam National University, Gwangju, 61186, Republic of Korea
| | - Young Sun Choi
- Jeollanam-do Agriculture Research and Extension Services Livestock Research Institute, Naju-si, Jeollanam-do, 58213, Republic of Korea
| | - Samuel Beck
- Department of Dermatology, Center for Aging Research, Chobanian & Avedisian School of Medicine, Boston University, Boston, 02118, USA.
| | - Sung-Hak Kim
- Animal Molecular Biochemistry Laboratory, Department of Animal Science, College of Agriculture and Life Sciences, Chonnam National University, Gwangju, 61186, Republic of Korea.
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11
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Feng Q, Dong Z, Nie R, Wang X. Identifying Diffuse Glioma Subtypes Based on Pathway Enrichment Evaluation. Interdiscip Sci 2024; 16:727-740. [PMID: 38637440 DOI: 10.1007/s12539-024-00627-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2023] [Revised: 03/04/2024] [Accepted: 03/06/2024] [Indexed: 04/20/2024]
Abstract
Gliomas are highly heterogeneous in molecular, histology, and microenvironment. However, a classification of gliomas by integrating different tumor microenvironment (TME) components remains unexplored. Based on the enrichment scores of 17 pathways involved in immune, stromal, DNA repair, and nervous system signatures in diffuse gliomas, we performed consensus clustering to uncover novel subtypes of gliomas. Consistently in three glioma datasets (TCGA-glioma, CGGA325, and CGGA301), we identified three subtypes: Stromal-enriched (Str-G), Nerve-enriched (Ner-G), and mixed (Mix-G). Ner-G was charactered by low immune infiltration levels, stromal contents, tumor mutation burden, copy number alterations, DNA repair activity, cell proliferation, epithelial-mesenchymal transformation, stemness, intratumor heterogeneity, androgen receptor expression and EGFR, PTEN, NF1 and MUC16 mutation rates, while high enrichment of neurons and nervous system pathways, and high tumor purity, estrogen receptor expression, IDH1 and CIC mutation rates, temozolomide response rate and overall and disease-free survival rates. In contrast, Str-G displayed contrastive characteristics to Ner-G. Our analysis indicates that the heterogeneity between glioma cells and neurons is lower than that between glioma cells and immune and stromal cells. Furthermore, the abundance of neurons is positively associated with clinical outcomes in gliomas, while the enrichment of immune and stromal cells has a negative association with them. Our classification method provides new insights into the tumor biology of gliomas, as well as clinical implications for the precise management of this disease.
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Affiliation(s)
- Qiushi Feng
- Biomedical Informatics Research Lab, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, 211198, China
- Institute of Innovative Drug Discovery and Development, China Pharmaceutical University, Nanjing, 211198, China
- Big Data Research Institute, China Pharmaceutical University, Nanjing, 211198, China
| | - Zehua Dong
- Biomedical Informatics Research Lab, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, 211198, China
- Institute of Innovative Drug Discovery and Development, China Pharmaceutical University, Nanjing, 211198, China
- Big Data Research Institute, China Pharmaceutical University, Nanjing, 211198, China
| | - Rongfang Nie
- Biomedical Informatics Research Lab, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, 211198, China
- Institute of Innovative Drug Discovery and Development, China Pharmaceutical University, Nanjing, 211198, China
- Big Data Research Institute, China Pharmaceutical University, Nanjing, 211198, China
| | - Xiaosheng Wang
- Biomedical Informatics Research Lab, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, 211198, China.
- Institute of Innovative Drug Discovery and Development, China Pharmaceutical University, Nanjing, 211198, China.
- Big Data Research Institute, China Pharmaceutical University, Nanjing, 211198, China.
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Wu Q, Berglund AE, Macaulay RJ, Etame AB. The Role of Mesenchymal Reprogramming in Malignant Clonal Evolution and Intra-Tumoral Heterogeneity in Glioblastoma. Cells 2024; 13:942. [PMID: 38891074 PMCID: PMC11171993 DOI: 10.3390/cells13110942] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2024] [Revised: 05/26/2024] [Accepted: 05/29/2024] [Indexed: 06/21/2024] Open
Abstract
Glioblastoma (GBM) is the most common yet uniformly fatal adult brain cancer. Intra-tumoral molecular and cellular heterogeneities are major contributory factors to therapeutic refractoriness and futility in GBM. Molecular heterogeneity is represented through molecular subtype clusters whereby the proneural (PN) subtype is associated with significantly increased long-term survival compared to the highly resistant mesenchymal (MES) subtype. Furthermore, it is universally recognized that a small subset of GBM cells known as GBM stem cells (GSCs) serve as reservoirs for tumor recurrence and progression. The clonal evolution of GSC molecular subtypes in response to therapy drives intra-tumoral heterogeneity and remains a critical determinant of GBM outcomes. In particular, the intra-tumoral MES reprogramming of GSCs using current GBM therapies has emerged as a leading hypothesis for therapeutic refractoriness. Preventing the intra-tumoral divergent evolution of GBM toward the MES subtype via new treatments would dramatically improve long-term survival for GBM patients and have a significant impact on GBM outcomes. In this review, we examine the challenges of the role of MES reprogramming in the malignant clonal evolution of glioblastoma and provide future perspectives for addressing the unmet therapeutic need to overcome resistance in GBM.
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Affiliation(s)
- Qiong Wu
- Department of Neuro-Oncology, H. Lee Moffitt Cancer Center and Research Institute, 12902 Magnolia Drive, Tampa, FL 33612, USA
| | - Anders E. Berglund
- Department of Biostatistics and Bioinformatics, H. Lee Moffitt Cancer Center and Research Institute, 12902 Magnolia Drive, Tampa, FL 33612, USA
| | - Robert J. Macaulay
- Departments of Anatomic Pathology, H. Lee Moffitt Cancer Center and Research Institute, 12902 Magnolia Drive, Tampa, FL 33612, USA
| | - Arnold B. Etame
- Department of Neuro-Oncology, H. Lee Moffitt Cancer Center and Research Institute, 12902 Magnolia Drive, Tampa, FL 33612, USA
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Wang J, Li X, Wang K, Li K, Gao Y, Xu J, Peng R, Zhang X, Zhang S, Zhou Y, Xu S, Zhang J. CLEC7A regulates M2 macrophages to suppress the immune microenvironment and implies poorer prognosis of glioma. Front Immunol 2024; 15:1361351. [PMID: 38846954 PMCID: PMC11153702 DOI: 10.3389/fimmu.2024.1361351] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/25/2023] [Accepted: 05/08/2024] [Indexed: 06/09/2024] Open
Abstract
Background Gliomas constitute a category of malignant tumors originating from brain tissue, representing the majority of intracranial malignancies. Previous research has demonstrated the pivotal role of CLEC7A in the progression of various cancers, yet its specific implications within gliomas remain elusive. The primary objective of this study was to investigate the prognostic significance and immune therapeutic potential of CLEC7A in gliomas through the integration of bioinformatics and clinical pathological analyses. Methods This investigation involved examining and validating the relationship between CLEC7A and glioma using samples from Hospital, along with data from TCGA, GEO, GTEx, and CGGA datasets. Subsequently, we explored its prognostic value, biological functions, expression location, and impact on immune cells within gliomas. Finally, we investigated its potential impact on the chemotaxis and polarization of macrophages. Results The expression of CLEC7A is upregulated in gliomas, and its levels escalate with the malignancy of tumors, establishing it as an independent prognostic factor. Functional enrichment analysis revealed a significant correlation between CLEC7A and immune function. Subsequent examination of immune cell differential expression demonstrated a robust association between CLEC7A and M2 macrophages. This conclusion was further substantiated through single-cell analysis, immunofluorescence, and correlation studies. Finally, the knockout of CLEC7A in M2 macrophages resulted in a noteworthy reduction in macrophage chemotaxis and polarization factors. Conclusion CLEC7A expression is intricately linked to the pathology and molecular characteristics of gliomas, establishing its role as an independent prognostic factor for gliomas and influencing macrophage function. It could be a promising target for immunotherapy in gliomas.
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Affiliation(s)
- Jinchao Wang
- Key Laboratory of Post-Neuro Injury, Neuro-repair and Regeneration in Central Nervous System, Ministry of Education and Tianjin City, Tianjin Neurological Institute, Tianjin Medical University General Hospital, Tianjin Medical University, Tianjin, China
| | - Xiaoru Li
- Department of Neurosurgery, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Shandong First Medical University, Jinan, China
| | - Kai Wang
- Department of Neurosurgery, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Shandong First Medical University, Jinan, China
| | - Kaiji Li
- Key Laboratory of Post-Neuro Injury, Neuro-repair and Regeneration in Central Nervous System, Ministry of Education and Tianjin City, Tianjin Neurological Institute, Tianjin Medical University General Hospital, Tianjin Medical University, Tianjin, China
| | - Yalong Gao
- Department of Neurosurgery, Tianjin Huanhu Hospital, Tianjin, China
| | - Jianye Xu
- Key Laboratory of Post-Neuro Injury, Neuro-repair and Regeneration in Central Nervous System, Ministry of Education and Tianjin City, Tianjin Neurological Institute, Tianjin Medical University General Hospital, Tianjin Medical University, Tianjin, China
| | - Ruilong Peng
- Key Laboratory of Post-Neuro Injury, Neuro-repair and Regeneration in Central Nervous System, Ministry of Education and Tianjin City, Tianjin Neurological Institute, Tianjin Medical University General Hospital, Tianjin Medical University, Tianjin, China
| | - Xu Zhang
- School of Medicine, Nankai University, Tianjin, China
| | - Shu Zhang
- Key Laboratory of Post-Neuro Injury, Neuro-repair and Regeneration in Central Nervous System, Ministry of Education and Tianjin City, Tianjin Neurological Institute, Tianjin Medical University General Hospital, Tianjin Medical University, Tianjin, China
| | - Yuan Zhou
- Department of Neurosurgery, Tianjin Medical University General Hospital, Tianjin, China
| | - Shangchen Xu
- Department of Neurosurgery, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Shandong First Medical University, Jinan, China
| | - Jianning Zhang
- Key Laboratory of Post-Neuro Injury, Neuro-repair and Regeneration in Central Nervous System, Ministry of Education and Tianjin City, Tianjin Neurological Institute, Tianjin Medical University General Hospital, Tianjin Medical University, Tianjin, China
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Stepanenko AA, Sosnovtseva AO, Valikhov MP, Chernysheva AA, Abramova OV, Pavlov KA, Chekhonin VP. Systemic and local immunosuppression in glioblastoma and its prognostic significance. Front Immunol 2024; 15:1326753. [PMID: 38481999 PMCID: PMC10932993 DOI: 10.3389/fimmu.2024.1326753] [Citation(s) in RCA: 9] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2023] [Accepted: 02/06/2024] [Indexed: 04/07/2024] Open
Abstract
The effectiveness of tumor therapy, especially immunotherapy and oncolytic virotherapy, critically depends on the activity of the host immune cells. However, various local and systemic mechanisms of immunosuppression operate in cancer patients. Tumor-associated immunosuppression involves deregulation of many components of immunity, including a decrease in the number of T lymphocytes (lymphopenia), an increase in the levels or ratios of circulating and tumor-infiltrating immunosuppressive subsets [e.g., macrophages, microglia, myeloid-derived suppressor cells (MDSCs), and regulatory T cells (Tregs)], as well as defective functions of subsets of antigen-presenting, helper and effector immune cell due to altered expression of various soluble and membrane proteins (receptors, costimulatory molecules, and cytokines). In this review, we specifically focus on data from patients with glioblastoma/glioma before standard chemoradiotherapy. We discuss glioblastoma-related immunosuppression at baseline and the prognostic significance of different subsets of circulating and tumor-infiltrating immune cells (lymphocytes, CD4+ and CD8+ T cells, Tregs, natural killer (NK) cells, neutrophils, macrophages, MDSCs, and dendritic cells), including neutrophil-to-lymphocyte ratio (NLR), focus on the immune landscape and prognostic significance of isocitrate dehydrogenase (IDH)-mutant gliomas, proneural, classical and mesenchymal molecular subtypes, and highlight the features of immune surveillance in the brain. All attempts to identify a reliable prognostic immune marker in glioblastoma tissue have led to contradictory results, which can be explained, among other things, by the unprecedented level of spatial heterogeneity of the immune infiltrate and the significant phenotypic diversity and (dys)functional states of immune subpopulations. High NLR is one of the most repeatedly confirmed independent prognostic factors for shorter overall survival in patients with glioblastoma and carcinoma, and its combination with other markers of the immune response or systemic inflammation significantly improves the accuracy of prediction; however, more prospective studies are needed to confirm the prognostic/predictive power of NLR. We call for the inclusion of dynamic assessment of NLR and other blood inflammatory markers (e.g., absolute/total lymphocyte count, platelet-to-lymphocyte ratio, lymphocyte-to-monocyte ratio, systemic immune-inflammation index, and systemic immune response index) in all neuro-oncology studies for rigorous evaluation and comparison of their individual and combinatorial prognostic/predictive significance and relative superiority.
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Affiliation(s)
- Aleksei A. Stepanenko
- Department of Fundamental and Applied Neurobiology, V. P. Serbsky National Medical Research Center of Psychiatry and Narcology, the Ministry of Health of the Russian Federation, Moscow, Russia
- Department of Medical Nanobiotechnology, Institute of Translational Medicine, N. I. Pirogov Russian National Research Medical University, The Ministry of Health of the Russian Federation, Moscow, Russia
| | - Anastasiia O. Sosnovtseva
- Department of Fundamental and Applied Neurobiology, V. P. Serbsky National Medical Research Center of Psychiatry and Narcology, the Ministry of Health of the Russian Federation, Moscow, Russia
- Center for Precision Genome Editing and Genetic Technologies for Biomedicine, Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Moscow, Russia
| | - Marat P. Valikhov
- Department of Fundamental and Applied Neurobiology, V. P. Serbsky National Medical Research Center of Psychiatry and Narcology, the Ministry of Health of the Russian Federation, Moscow, Russia
- Department of Medical Nanobiotechnology, Institute of Translational Medicine, N. I. Pirogov Russian National Research Medical University, The Ministry of Health of the Russian Federation, Moscow, Russia
| | - Anastasia A. Chernysheva
- Department of Fundamental and Applied Neurobiology, V. P. Serbsky National Medical Research Center of Psychiatry and Narcology, the Ministry of Health of the Russian Federation, Moscow, Russia
| | - Olga V. Abramova
- Department of Fundamental and Applied Neurobiology, V. P. Serbsky National Medical Research Center of Psychiatry and Narcology, the Ministry of Health of the Russian Federation, Moscow, Russia
| | - Konstantin A. Pavlov
- Department of Fundamental and Applied Neurobiology, V. P. Serbsky National Medical Research Center of Psychiatry and Narcology, the Ministry of Health of the Russian Federation, Moscow, Russia
| | - Vladimir P. Chekhonin
- Department of Fundamental and Applied Neurobiology, V. P. Serbsky National Medical Research Center of Psychiatry and Narcology, the Ministry of Health of the Russian Federation, Moscow, Russia
- Department of Medical Nanobiotechnology, Institute of Translational Medicine, N. I. Pirogov Russian National Research Medical University, The Ministry of Health of the Russian Federation, Moscow, Russia
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15
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Boskovic P, Wilke N, Man KH, Lichter P, Francois L, Radlwimmer B. Branched-chain amino acid transaminase 1 regulates glioblastoma cell plasticity and contributes to immunosuppression. Neuro Oncol 2024; 26:251-265. [PMID: 37769206 PMCID: PMC10836774 DOI: 10.1093/neuonc/noad190] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2023] [Indexed: 09/30/2023] Open
Abstract
BACKGROUND Glioblastoma is the most common malignant brain tumor in adults. Cellular plasticity and the poorly differentiated features result in a fast relapse of the tumors following treatment. Moreover, the immunosuppressive microenvironment proved to be a major obstacle to immunotherapeutic approaches. Branched-chain amino acid transaminase 1 (BCAT1) was shown to drive the growth of glioblastoma and other cancers;however, its oncogenic mechanism remains poorly understood. METHODS Using human tumor data, cell line models and orthotopic immuno-competent and -deficient mouse models, we investigated the phenotypic and mechanistic effects of BCAT1 on glioblastoma cell state and immunomodulation. RESULTS Here, we show that BCAT1 is crucial for maintaining the poorly differentiated state of glioblastoma cells and that its low expression correlates with a more differentiated glioblastoma phenotype. Furthermore, orthotopic tumor injection into immunocompetent mice demonstrated that the brain microenvironment is sufficient to induce differentiation of Bcat1-KO tumors in vivo. We link the transition to a differentiated cell state to the increased activity of ten-eleven translocation demethylases and the hypomethylation and activation of neuronal differentiation genes. In addition, the knockout of Bcat1 attenuated immunosuppression, allowing for an extensive infiltration of CD8+ cytotoxic T-cells and complete abrogation of tumor growth. Further analysis in immunodeficient mice revealed that both tumor cell differentiation and immunomodulation following BCAT1-KO contribute to the long-term suppression of tumor growth. CONCLUSIONS Our study unveils BCAT1's pivotal role in promoting glioblastoma growth by inhibiting tumor cell differentiation and sustaining an immunosuppressive milieu. These findings offer a novel therapeutic avenue for targeting glioblastoma through the inhibition of BCAT1.
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Affiliation(s)
- Pavle Boskovic
- Division of Molecular Genetics, German Cancer Research Center (DKFZ), Heidelberg, Germany
- Faculty of Biosciences, Heidelberg University, Heidelberg, Germany
| | - Nathalie Wilke
- Division of Molecular Genetics, German Cancer Research Center (DKFZ), Heidelberg, Germany
- Faculty of Biosciences, Heidelberg University, Heidelberg, Germany
| | - Ka-Hou Man
- Division of Molecular Genetics, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Peter Lichter
- Division of Molecular Genetics, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Liliana Francois
- Division of Molecular Genetics, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Bernhard Radlwimmer
- Division of Molecular Genetics, German Cancer Research Center (DKFZ), Heidelberg, Germany
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16
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Yu W, Zhou M, Niu H, Li J, Li Q, Xu X, Liang F, Rui C. Prognostic marker CXCL5 in glioblastoma polyformis and its mechanism of immune invasion. BMC Cancer 2024; 24:140. [PMID: 38287266 PMCID: PMC10823677 DOI: 10.1186/s12885-023-11650-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2023] [Accepted: 11/17/2023] [Indexed: 01/31/2024] Open
Abstract
Glioblastoma multiforme (GBM) is the most aggressive brain cancer with a poor prognosis. Therefore, the correlative molecular markers and molecular mechanisms should be explored to assess the occurrence and treatment of glioma.WB and qPCR assays were used to detect the expression of CXCL5 in human GBM tissues. The relationship between CXCL5 expression and clinicopathological features was evaluated using logistic regression analysis, Wilcoxon symbolic rank test, and Kruskal-Wallis test. Univariate, multivariate Cox regression and Kaplan-Meier methods were used to assess CXCL5 and other prognostic factors of GBM. Gene set enrichment analysis (GSEA) was used to identify pathways associated with CXCL5. The correlation between CXCL5 and tumor immunoinfiltration was investigated using single sample gene set enrichment analysis (ssGSEA) of TCGA data. Cell experiments and mouse subcutaneous transplanted tumor models were used to evaluate the role of CXCL5 in GBM. WB, qPCR, immunofluorescence, and immunohistochemical assays showed that CXCL5 expression was increased in human GBM tissues. Furthermore, high CXCL5 expression was closely related to poor disease-specific survival and overall survival of GBM patients. The ssGSEA suggested that CXCL5 is closely related to the cell cycle and immune response through PPAR signaling pathway. GSEA also showed that CXCL5 expression was positively correlated with macrophage cell infiltration level and negatively correlated with cytotoxic cell infiltration level. CXCL5 may be associated with the prognosis and immunoinfiltration of GBM.
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Affiliation(s)
- Wangyang Yu
- Union Hospital Affiliated to Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Minfeng Zhou
- Union Hospital Affiliated to Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Huifang Niu
- College of Food Science and Technology, Huazhong Agricultural University, Wuhan, China
- Suizhou Hospital of Traditional Chinese Medicine, Suizhou, China
| | - Jinxiao Li
- Union Hospital Affiliated to Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Qiumeng Li
- Union Hospital Affiliated to Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Xiaoyun Xu
- College of Food Science and Technology, Huazhong Agricultural University, Wuhan, China.
| | - Fengxia Liang
- School of Acupuncture and Bone Injury, Hubei University of Chinese Medicine, Wuhan, China.
| | - Chen Rui
- Union Hospital Affiliated to Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
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17
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Shen S, Liu X, Guo Q, Liang Q, Wu J, Guan G, Zou C, Zhu C, Yan Z, Liu T, Chen L, Cheng P, Cheng W, Wu A. Tumor microenvironment remodeling plus immunotherapy could be used in mesenchymal-like tumor with high tumor residual and drug resistant rate. Commun Biol 2023; 6:1281. [PMID: 38110614 PMCID: PMC10728080 DOI: 10.1038/s42003-023-05667-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2022] [Accepted: 12/04/2023] [Indexed: 12/20/2023] Open
Abstract
Epithelial-mesenchymal transition (EMT) is a common process during tumor progression and is always related to residual tumor, drug resistance and immune suppression. However, considering the heterogeneity in EMT process, there is still a need to establish robust EMT classification system with reasonable molecular, biological and clinical implications to investigate whether these unfavorable survival factors are common or unique in different individuals. In our work, we classify tumors with four EMT status, that is, EMTlow, EMTmid, EMThigh-NOS (Not Otherwise Specified), and EMThigh-AKT (AKT pathway overactivation) subtypes. We find that EMThigh-NOS subtype is driven by intrinsic somatic alterations. While, EMThigh-AKT subtype is maintained by extrinsic cellular interplay between tumor cells and macrophages in an AKT-dependent manner. EMThigh-AKT subtype is both unresectable and drug resistant while EMThigh-NOS subtype can be treated with cell cycle related drugs. Importantly, AKT activation in EMThigh-AKT not only enhances EMT process, but also contributes to the immunosuppressive microenvironment. By remodeling tumor immune-microenvironment by AKT inhibition, EMThigh-AKT can be treated by immune checkpoint blockade therapies. Meanwhile, we develop TumorMT website ( http://tumormt.neuroscience.org.cn/ ) to apply this EMT classification and provide reasonable therapeutic guidance.
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Affiliation(s)
- Shuai Shen
- Department of Neurosurgery, Shengjing Hospital of China Medical University, Shenyang, Liaoning, China
| | - Xing Liu
- Department of Neurosurgery, Shengjing Hospital of China Medical University, Shenyang, Liaoning, China
| | - Qing Guo
- Department of Neurosurgery, Shengjing Hospital of China Medical University, Shenyang, Liaoning, China
| | - Qingyu Liang
- Department of Neurosurgery, The First Hospital of China Medical University, Shenyang, Liaoning, China
| | - Jianqi Wu
- Department of Neurosurgery, Shengjing Hospital of China Medical University, Shenyang, Liaoning, China
| | - Gefei Guan
- Department of Neurosurgery, The First Hospital of China Medical University, Shenyang, Liaoning, China
| | - Cunyi Zou
- Department of Neurosurgery, The First Hospital of China Medical University, Shenyang, Liaoning, China
| | - Chen Zhu
- Department of Neurosurgery, The First Hospital of China Medical University, Shenyang, Liaoning, China
| | - Zihao Yan
- Department of Neurosurgery, The First Hospital of China Medical University, Shenyang, Liaoning, China
| | - Tianqi Liu
- Department of Neurosurgery, Shengjing Hospital of China Medical University, Shenyang, Liaoning, China
| | - Ling Chen
- Department of Neurosurgery, Chinese People's Liberation Army of China (PLA) General Hospital, Medical School of Chinese PLA, Institute of Neurosurgery of Chinese PLA, Beijing, China
| | - Peng Cheng
- Department of Neurosurgery, The First Hospital of China Medical University, Shenyang, Liaoning, China.
| | - Wen Cheng
- Department of Neurosurgery, Shengjing Hospital of China Medical University, Shenyang, Liaoning, China.
| | - Anhua Wu
- Department of Neurosurgery, Shengjing Hospital of China Medical University, Shenyang, Liaoning, China.
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18
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Lee J, Narang S, Martinez J, Rao G, Rao A. Association of graph-based spatial features with overall survival status of glioblastoma patients. Sci Rep 2023; 13:17046. [PMID: 37813981 PMCID: PMC10562480 DOI: 10.1038/s41598-023-44353-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2022] [Accepted: 10/06/2023] [Indexed: 10/11/2023] Open
Abstract
Glioblastoma is the most common malignant brain tumor with less than 15 months median survival. To aid prognosis, there is a need for decision tools that leverage diagnostic modalities such as MRI to inform survival. In this study, we examine higher-order spatial proximity characteristics from habitats and propose two graph-based methods (minimum spanning tree and graph run-length matrix) to characterize spatial heterogeneity over tumor MRI-derived intensity habitats and assess their relationships with overall survival as well as the immune signature status of patients with glioblastoma. A data set of 74 patients was studied based on the availability of post-contrast T1-weighted and T2-weighted fluid attenuated inversion recovery (FLAIR) image data in The Cancer Image Archive (TCIA). We assessed the predictive value of MST- and GRLM-derived features from 2D images for prediction of 12-month survival status and immune signature status of patients with glioblastoma via a receiver operating characteristic curve analysis. For 12-month survival prediction using MST-based method, sensitivity and specificity were 0.82 and 0.79 respectively. For GRLM-based method, sensitivity and specificity were 0.73 and 0.77 respectively. For immune status, sensitivity and specificity were 0.91 and 0.69, respectively, for the GRLM-based method with an immune effector. Our results show that the proposed MST- and GRLM-derived features are predictive of 12-month survival status as well as the immune signature status of patients with glioblastoma. To our knowledge, this is the first application of MST- and GRLM-based proximity analyses for the study of radiologically-defined tumor habitats in glioblastoma.
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Affiliation(s)
- Joonsang Lee
- Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI, 48109, USA.
- Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
| | - Shivali Narang
- Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Juan Martinez
- Department of Neurosurgery, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Ganesh Rao
- Department of Neurosurgery, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Arvind Rao
- Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI, 48109, USA.
- Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
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19
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Zaidi SE, Moelker E, Singh K, Mohan A, Salgado MA, Essibayi MA, Hotchkiss K, Shen S, Lee W, Sampson J, Khasraw M. Novel Immunotherapeutic Approaches for the Treatment of Glioblastoma. BioDrugs 2023; 37:489-503. [PMID: 37256535 DOI: 10.1007/s40259-023-00598-2] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/20/2023] [Indexed: 06/01/2023]
Abstract
Glioblastoma is highly aggressive and remains difficult to treat despite being the most common malignant primary brain tumor in adults. Current standard-of-care treatment calls for maximum resection of the tumor mass followed by concurrent chemotherapy and radiotherapy and further adjuvant chemotherapy if necessary. Despite this regimen, prognosis remains grim. Immunotherapy has shown promising success in a variety of solid tumor types, but efficacy in glioblastoma is yet to be demonstrated. Barriers to the success of immunotherapy in glioblastoma include: a heterogeneous tumor cell population, a highly immunosuppressive microenvironment, and the blood-brain barrier, to name a few. Several immunotherapeutic approaches are actively being investigated and developed to overcome these limitations. In this review, we present different classes of immunotherapy targeting glioblastoma, their most recent results, and potential future directions.
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Affiliation(s)
- Saïf Eddine Zaidi
- Department of Neurosurgery, Duke University Medical Center, Preston Robert Tisch Brain Tumor Center at Duke, Durham, NC, USA
- School of Medicine, University of Paris Cité, Paris, France
| | - Eliese Moelker
- Department of Neurosurgery, Duke University Medical Center, Preston Robert Tisch Brain Tumor Center at Duke, Durham, NC, USA
| | - Kirit Singh
- Department of Neurosurgery, Duke University Medical Center, Preston Robert Tisch Brain Tumor Center at Duke, Durham, NC, USA
| | - Aditya Mohan
- Department of Neurosurgery, Duke University Medical Center, Preston Robert Tisch Brain Tumor Center at Duke, Durham, NC, USA
| | - Miguel A Salgado
- Department of Neurosurgery, Duke University Medical Center, Preston Robert Tisch Brain Tumor Center at Duke, Durham, NC, USA
| | - Muhammed Amir Essibayi
- Department of Neurosurgery, Albert Einstein College of Medicine, Bronx, NY, USA
- Department of Radiology, Mayo Clinic, Rochester, MN, USA
| | - Kelly Hotchkiss
- Department of Neurosurgery, Duke University Medical Center, Preston Robert Tisch Brain Tumor Center at Duke, Durham, NC, USA
| | - Steven Shen
- Department of Neurosurgery, Duke University Medical Center, Preston Robert Tisch Brain Tumor Center at Duke, Durham, NC, USA
| | - William Lee
- University of North Carolina, Chapel Hill, NC, USA
| | - John Sampson
- Department of Neurosurgery, Duke University Medical Center, Preston Robert Tisch Brain Tumor Center at Duke, Durham, NC, USA
| | - Mustafa Khasraw
- Department of Neurosurgery, Duke University Medical Center, Preston Robert Tisch Brain Tumor Center at Duke, Durham, NC, USA.
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20
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Ah-Pine F, Khettab M, Bedoui Y, Slama Y, Daniel M, Doray B, Gasque P. On the origin and development of glioblastoma: multifaceted role of perivascular mesenchymal stromal cells. Acta Neuropathol Commun 2023; 11:104. [PMID: 37355636 PMCID: PMC10290416 DOI: 10.1186/s40478-023-01605-x] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2023] [Accepted: 06/18/2023] [Indexed: 06/26/2023] Open
Abstract
Glioblastoma, IDH wild-type is the most common and aggressive form of glial tumors. The exact mechanisms of glioblastoma oncogenesis, including the identification of the glioma-initiating cell, are yet to be discovered. Recent studies have led to the hypothesis that glioblastoma arises from neural stem cells and glial precursor cells and that cell lineage constitutes a key determinant of the glioblastoma molecular subtype. These findings brought significant advancement to the comprehension of gliomagenesis. However, the cellular origin of glioblastoma with mesenchymal molecular features remains elusive. Mesenchymal stromal cells emerge as potential glioblastoma-initiating cells, especially with regard to the mesenchymal molecular subtype. These fibroblast-like cells, which derive from the neural crest and reside in the perivascular niche, may underlie gliomagenesis and exert pro-tumoral effects within the tumor microenvironment. This review synthesizes the potential roles of mesenchymal stromal cells in the context of glioblastoma and provides novel research avenues to better understand this lethal disease.
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Affiliation(s)
- F. Ah-Pine
- Unité de Recherche en Pharmaco-Immunologie (UR-EPI), Université et CHU de La Réunion, 97400 Saint-Denis, France
- Service d’Anatomie et Cytologie Pathologiques, CHU de La Réunion sites SUD – Saint-Pierre, BP 350, 97448 Saint-Pierre Cedex, France
| | - M. Khettab
- Unité de Recherche en Pharmaco-Immunologie (UR-EPI), Université et CHU de La Réunion, 97400 Saint-Denis, France
- Service d’Oncologie Médicale, CHU de La Réunion sites SUD – Saint-Pierre, BP 350, 97448 Saint-Pierre Cedex, France
| | - Y. Bedoui
- Unité de Recherche en Pharmaco-Immunologie (UR-EPI), Université et CHU de La Réunion, 97400 Saint-Denis, France
- Service d’Anatomie et Cytologie Pathologiques, CHU de La Réunion sites SUD – Saint-Pierre, BP 350, 97448 Saint-Pierre Cedex, France
| | - Y. Slama
- Unité de Recherche en Pharmaco-Immunologie (UR-EPI), Université et CHU de La Réunion, 97400 Saint-Denis, France
| | - M. Daniel
- Unité de Recherche en Pharmaco-Immunologie (UR-EPI), Université et CHU de La Réunion, 97400 Saint-Denis, France
- Service de Médecine d’Urgences-SAMU-SMUR, CHU de La Réunion - Site Félix Guyon, Allée Des Topazes CS 11 021, 97400 Saint-Denis, France
| | - B. Doray
- Unité de Recherche en Pharmaco-Immunologie (UR-EPI), Université et CHU de La Réunion, 97400 Saint-Denis, France
- Service de Génétique, CHU de La Réunion - Site Félix Guyon, Allée Des Topazes CS 11 021, 97400 Saint-Denis, France
| | - P. Gasque
- Unité de Recherche en Pharmaco-Immunologie (UR-EPI), Université et CHU de La Réunion, 97400 Saint-Denis, France
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21
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Menevse AN, Ammer LM, Vollmann-Zwerenz A, Kupczyk M, Lorenz J, Weidner L, Hussein A, Sax J, Mühlbauer J, Heuschneider N, Rohrmus C, Mai LS, Jachnik B, Stamova S, Volpin V, Durst FC, Sorrentino A, Xydia M, Milenkovic VM, Bader S, Braun FK, Wetzel C, Albert NL, Tonn JC, Bartenstein P, Proescholdt M, Schmidt NO, Linker RA, Riemenschneider MJ, Beckhove P, Hau P. TSPO acts as an immune resistance gene involved in the T cell mediated immune control of glioblastoma. Acta Neuropathol Commun 2023; 11:75. [PMID: 37158962 PMCID: PMC10165826 DOI: 10.1186/s40478-023-01550-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2023] [Accepted: 03/14/2023] [Indexed: 05/10/2023] Open
Abstract
Glioblastoma (GB) IDH-wildtype is the most malignant primary brain tumor. It is particularly resistant to current immunotherapies. Translocator protein 18 kDa (TSPO) is upregulated in GB and correlates with malignancy and poor prognosis, but also with increased immune infiltration. Here, we studied the role of TSPO in the regulation of immune resistance of human GB cells. The role of TSPO in tumor immune resistance was experimentally determined in primary brain tumor initiating cells (BTICs) and cell lines through genetic manipulation of TSPO expression and subsequent cocultures with antigen specific cytotoxic T cells and autologous tumor-infiltrating T cells. Death inducing intrinsic and extrinsic apoptotic pathways affected by TSPO were investigated. TSPO-regulated genes mediating apoptosis resistance in BTICs were identified through gene expression analysis and subsequent functional analyses. TSPO transcription in primary GB cells correlated with CD8+ T cell infiltration, cytotoxic activity of T cell infiltrate, expression of TNFR and IFNGR and with the activity of their downstream signalling pathways, as well as with the expression of TRAIL receptors. Coculture of BTICs with tumor reactive cytotoxic T cells or with T cell-derived factors induced TSPO up-regulation through T cell derived TNFα and IFNγ. Silencing of TSPO sensitized BTICs against T cell-mediated cytotoxicity. TSPO selectively protected BTICs against TRAIL-induced apoptosis by regulating apoptosis pathways. TSPO also regulated the expression of multiple genes associated with resistance against apoptosis. We conclude that TSPO expression in GB is induced through T cell-derived cytokines TNFα and IFNγ and that TSPO expression protects GB cells against cytotoxic T cell attack through TRAIL. Our data thereby provide an indication that therapeutic targeting of TSPO may be a suitable approach to sensitize GB to immune cell-mediated cytotoxicity by circumventing tumor intrinsic TRAIL resistance.
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Affiliation(s)
- Ayse N Menevse
- Division of Interventional Immunology, Leibniz Institute for Immunotherapy (LIT), 93053, Regensburg, Germany
| | - Laura-Marie Ammer
- Wilhelm Sander-NeuroOncology Unit and Department of Neurology, University Hospital Regensburg, 93053, Regensburg, Germany
| | - Arabel Vollmann-Zwerenz
- Wilhelm Sander-NeuroOncology Unit and Department of Neurology, University Hospital Regensburg, 93053, Regensburg, Germany
| | - Marcell Kupczyk
- Division of Interventional Immunology, Leibniz Institute for Immunotherapy (LIT), 93053, Regensburg, Germany
| | - Julia Lorenz
- Department of Neuropathology, University Hospital Regensburg, 93053, Regensburg, Germany
| | - Lorraine Weidner
- Department of Neuropathology, University Hospital Regensburg, 93053, Regensburg, Germany
| | - Abir Hussein
- Division of Interventional Immunology, Leibniz Institute for Immunotherapy (LIT), 93053, Regensburg, Germany
| | - Julian Sax
- Division of Interventional Immunology, Leibniz Institute for Immunotherapy (LIT), 93053, Regensburg, Germany
| | - Jasmin Mühlbauer
- Division of Interventional Immunology, Leibniz Institute for Immunotherapy (LIT), 93053, Regensburg, Germany
| | - Nicole Heuschneider
- Division of Interventional Immunology, Leibniz Institute for Immunotherapy (LIT), 93053, Regensburg, Germany
| | - Celine Rohrmus
- Wilhelm Sander-NeuroOncology Unit and Department of Neurology, University Hospital Regensburg, 93053, Regensburg, Germany
| | - Laura S Mai
- Wilhelm Sander-NeuroOncology Unit and Department of Neurology, University Hospital Regensburg, 93053, Regensburg, Germany
| | - Birgit Jachnik
- Wilhelm Sander-NeuroOncology Unit and Department of Neurology, University Hospital Regensburg, 93053, Regensburg, Germany
| | - Slava Stamova
- Division of Interventional Immunology, Leibniz Institute for Immunotherapy (LIT), 93053, Regensburg, Germany
| | - Valentina Volpin
- Division of Interventional Immunology, Leibniz Institute for Immunotherapy (LIT), 93053, Regensburg, Germany
| | - Franziska C Durst
- Division of Interventional Immunology, Leibniz Institute for Immunotherapy (LIT), 93053, Regensburg, Germany
| | - Antonio Sorrentino
- Division of Interventional Immunology, Leibniz Institute for Immunotherapy (LIT), 93053, Regensburg, Germany
| | - Maria Xydia
- Division of Interventional Immunology, Leibniz Institute for Immunotherapy (LIT), 93053, Regensburg, Germany
| | - Vladimir M Milenkovic
- Department of Psychiatry and Psychotherapy, University of Regensburg, Molecular Neurosciences, 93053, Regensburg, Germany
| | - Stefanie Bader
- Department of Psychiatry and Psychotherapy, University of Regensburg, Molecular Neurosciences, 93053, Regensburg, Germany
| | - Frank K Braun
- Department of Neuropathology, University Hospital Regensburg, 93053, Regensburg, Germany
| | - Christian Wetzel
- Department of Psychiatry and Psychotherapy, University of Regensburg, Molecular Neurosciences, 93053, Regensburg, Germany
| | - Nathalie L Albert
- Department of Nuclear Medicine, University Hospital of Munich, LMU Munich, 80336, Munich, Germany
| | - Joerg-Christian Tonn
- Department of Neurosurgery, University Hospital of Munich, LMU Munich, 80336, Munich, Germany
| | - Peter Bartenstein
- Department of Nuclear Medicine, University Hospital of Munich, LMU Munich, 80336, Munich, Germany
| | - Martin Proescholdt
- Wilhelm Sander-NeuroOncology Unit and Department of Neurology, University Hospital Regensburg, 93053, Regensburg, Germany
- Department of Neurosurgery, University Hospital Regensburg, 93053, Regensburg, Germany
| | - Nils O Schmidt
- Wilhelm Sander-NeuroOncology Unit and Department of Neurology, University Hospital Regensburg, 93053, Regensburg, Germany
- Department of Neurosurgery, University Hospital Regensburg, 93053, Regensburg, Germany
| | - Ralf A Linker
- Department of Neurology, University Hospital Regensburg, 93053, Regensburg, Germany
| | | | - Philipp Beckhove
- Division of Interventional Immunology, Leibniz Institute for Immunotherapy (LIT), 93053, Regensburg, Germany.
- Department of Internal Medicine III, University Hospital Regensburg, 93053, Regensburg, Germany.
- LIT - Leibniz Institute for Immunotherapy (former RCI), c/o Universitätsklinikum Regensburg, Franz-Josef-Strauß-Allee 11, 93053, Regensburg, Germany.
| | - Peter Hau
- Wilhelm Sander-NeuroOncology Unit and Department of Neurology, University Hospital Regensburg, 93053, Regensburg, Germany.
- Department of Neurology -NeuroOncology, University Hospital Regensburg, Franz-Josef-Strauß-Allee 11, 93053, Regensburg, Germany.
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22
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Wu H, Liang B, Chen Z, Zhang H. MultiSimNeNc: A network representation learning-based module identification method by network embedding and clustering. Comput Biol Med 2023; 156:106703. [PMID: 36889026 DOI: 10.1016/j.compbiomed.2023.106703] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2022] [Revised: 02/05/2023] [Accepted: 02/19/2023] [Indexed: 02/26/2023]
Abstract
Accurate identification of gene modules based on biological networks is an effective approach to understanding gene patterns of cancer from a module-level perspective. However, most graph clustering algorithms just consider low-order topological connectivity, which limits their accuracy in gene module identification. In this study, we propose a novel network-based method, MultiSimNeNc, to identify modules in various types of networks by integrating network representation learning (NRL) and clustering algorithms. In this method, we first obtain the multi-order similarity of the network using graph convolution (GC). Then, we aggregate the multi-order similarity to characterize the network structure and use non-negative matrix factorization (NMF) to achieve low-dimensional node characterization. Finally, we predict the number of modules based on the bayesian information criterion (BIC) and use the gaussian mixture model (GMM) to identify modules. To testify to the efficacy of MultiSimeNc in module identification, we apply this method to two types of biological networks and six benchmark networks, where the biological networks are constructed based on the fusion of multi-omics data from glioblastoma (GBM). The analysis shows that MultiSimNeNc outperforms several state-of-the-art module identification algorithms in identification accuracy, which is an effective method for understanding biomolecular mechanisms of pathogenesis from a module-level perspective.
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Affiliation(s)
- Hao Wu
- College of Information Engineering, Northwest A&F University, 712100, Yangling, China; School of Software, Shandong University, 250100, Jinan, China.
| | - Biting Liang
- College of Information Engineering, Northwest A&F University, 712100, Yangling, China
| | - Zhongli Chen
- Tibet Center for Disease Control and Prevention, the People's Government of Tibet Autonomous Region, 850000, Lhasa, China
| | - Hongming Zhang
- College of Information Engineering, Northwest A&F University, 712100, Yangling, China.
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23
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Khan F, Pang L, Dunterman M, Lesniak MS, Heimberger AB, Chen P. Macrophages and microglia in glioblastoma: heterogeneity, plasticity, and therapy. J Clin Invest 2023; 133:163446. [PMID: 36594466 PMCID: PMC9797335 DOI: 10.1172/jci163446] [Citation(s) in RCA: 164] [Impact Index Per Article: 82.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2023] Open
Abstract
Glioblastoma (GBM) is the most aggressive tumor in the central nervous system and contains a highly immunosuppressive tumor microenvironment (TME). Tumor-associated macrophages and microglia (TAMs) are a dominant population of immune cells in the GBM TME that contribute to most GBM hallmarks, including immunosuppression. The understanding of TAMs in GBM has been limited by the lack of powerful tools to characterize them. However, recent progress on single-cell technologies offers an opportunity to precisely characterize TAMs at the single-cell level and identify new TAM subpopulations with specific tumor-modulatory functions in GBM. In this Review, we discuss TAM heterogeneity and plasticity in the TME and summarize current TAM-targeted therapeutic potential in GBM. We anticipate that the use of single-cell technologies followed by functional studies will accelerate the development of novel and effective TAM-targeted therapeutics for GBM patients.
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24
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Swan SL, Mehta N, Ilich E, Shen SH, Wilkinson DS, Anderson AR, Segura T, Sanchez-Perez L, Sampson JH, Bellamkonda RV. IL7 and IL7 Flt3L co-expressing CAR T cells improve therapeutic efficacy in mouse EGFRvIII heterogeneous glioblastoma. Front Immunol 2023; 14:1085547. [PMID: 36817432 PMCID: PMC9936235 DOI: 10.3389/fimmu.2023.1085547] [Citation(s) in RCA: 19] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2022] [Accepted: 01/04/2023] [Indexed: 02/05/2023] Open
Abstract
Chimeric antigen receptor (CAR) T cell therapy in glioblastoma faces many challenges including insufficient CAR T cell abundance and antigen-negative tumor cells evading targeting. Unfortunately, preclinical studies evaluating CAR T cells in glioblastoma focus on tumor models that express a single antigen, use immunocompromised animals, and/or pre-treat with lymphodepleting agents. While lymphodepletion enhances CAR T cell efficacy, it diminishes the endogenous immune system that has the potential for tumor eradication. Here, we engineered CAR T cells to express IL7 and/or Flt3L in 50% EGFRvIII-positive and -negative orthotopic tumors pre-conditioned with non-lymphodepleting irradiation. IL7 and IL7 Flt3L CAR T cells increased intratumoral CAR T cell abundance seven days after treatment. IL7 co-expression with Flt3L modestly increased conventional dendritic cells as well as the CD103+XCR1+ population known to have migratory and antigen cross-presenting capabilities. Treatment with IL7 or IL7 Flt3L CAR T cells improved overall survival to 67% and 50%, respectively, compared to 9% survival with conventional or Flt3L CAR T cells. We concluded that CAR T cells modified to express IL7 enhanced CAR T cell abundance and improved overall survival in EGFRvIII heterogeneous tumors pre-conditioned with non-lymphodepleting irradiation. Potentially IL7 or IL7 Flt3L CAR T cells can provide new opportunities to combine CAR T cells with other immunotherapies for the treatment of glioblastoma.
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Affiliation(s)
- Sheridan L Swan
- Department of Biomedical Engineering, Pratt School of Engineering, Duke University, Durham, NC, United States
| | - Nalini Mehta
- Department of Biomedical Engineering, Pratt School of Engineering, Duke University, Durham, NC, United States
| | - Ekaterina Ilich
- Department of Biomedical Engineering, Pratt School of Engineering, Duke University, Durham, NC, United States
| | - Steven H Shen
- Duke Brain Tumor Immunotherapy Program, Department of Neurosurgery, Duke University Medical Center, Durham, NC, United States.,The Preston Robert Tisch Brain Tumor Center, Duke University Medical Center, Durham, NC, United States.,Department of Pathology, Duke University Medical Center, Durham, NC, United States
| | - Daniel S Wilkinson
- Duke Brain Tumor Immunotherapy Program, Department of Neurosurgery, Duke University Medical Center, Durham, NC, United States
| | - Alexa R Anderson
- Department of Biomedical Engineering, Pratt School of Engineering, Duke University, Durham, NC, United States
| | - Tatiana Segura
- Department of Biomedical Engineering, Pratt School of Engineering, Duke University, Durham, NC, United States.,Clinical Science Departments of Neurology and Dermatology, Duke University, Durham, NC, United States
| | - Luis Sanchez-Perez
- Duke Brain Tumor Immunotherapy Program, Department of Neurosurgery, Duke University Medical Center, Durham, NC, United States.,The Preston Robert Tisch Brain Tumor Center, Duke University Medical Center, Durham, NC, United States.,Department of Neurosurgery, Duke University Medical Center, Durham, NC, United States
| | - John H Sampson
- Duke Brain Tumor Immunotherapy Program, Department of Neurosurgery, Duke University Medical Center, Durham, NC, United States.,The Preston Robert Tisch Brain Tumor Center, Duke University Medical Center, Durham, NC, United States.,Department of Pathology, Duke University Medical Center, Durham, NC, United States.,Department of Neurosurgery, Duke University Medical Center, Durham, NC, United States
| | - Ravi V Bellamkonda
- Department of Biology, Emory University, Atlanta, GA, United States.,Wallace H. Coulter Department of Biomedical Engineering, Emory University, Atlanta, GA, United States
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25
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Musatova OE, Rubtsov YP. Effects of glioblastoma-derived extracellular vesicles on the functions of immune cells. Front Cell Dev Biol 2023; 11:1060000. [PMID: 36960410 PMCID: PMC10028257 DOI: 10.3389/fcell.2023.1060000] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2022] [Accepted: 02/22/2023] [Indexed: 03/09/2023] Open
Abstract
Glioblastoma is the most aggressive variant of glioma, the tumor of glial origin which accounts for 80% of brain tumors. Glioblastoma is characterized by astoundingly poor prognosis for patients; a combination of surgery, chemo- and radiotherapy used for clinical treatment of glioblastoma almost inevitably results in rapid relapse and development of more aggressive and therapy resistant tumor. Recently, it was demonstrated that extracellular vesicles produced by glioblastoma (GBM-EVs) during apoptotic cell death can bind to surrounding cells and change their phenotype to more aggressive. GBM-EVs participate also in establishment of immune suppressive microenvironment that protects glioblastoma from antigen-specific recognition and killing by T cells. In this review, we collected present data concerning characterization of GBM-EVs and study of their effects on different populations of the immune cells (T cells, macrophages, dendritic cells, myeloid-derived suppressor cells). We aimed at critical analysis of experimental evidence in order to conclude whether glioblastoma-derived extracellular vesicles are a major factor in immune evasion of this deadly tumor. We summarized data concerning potential use of GBM-EVs for non-invasive diagnostics of glioblastoma. Finally, the applicability of approaches aimed at blocking of GBM-EVs production or their fusion with target cells for treatment of glioblastoma was analyzed.
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Affiliation(s)
- Oxana E. Musatova
- Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, RAS, Moscow, Russia
| | - Yury P. Rubtsov
- Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, RAS, Moscow, Russia
- N.N.Blokhin Russian Cancer Research Center, Ministry of Health of the Russian Federation, Moscow, Russia
- *Correspondence: Yury P. Rubtsov,
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26
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Cascão R, Faria CC. Optimizing the role of immunotherapy for the treatment of glioblastoma. NEW INSIGHTS INTO GLIOBLASTOMA 2023:553-591. [DOI: 10.1016/b978-0-323-99873-4.00012-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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27
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Liu Z, Wu J, Ji H, Zhao H, Wang F, Dong J, Zhang J, Wang N, Yan X, Wang K, Hu S. Stromal protein CCN family contributes to the poor prognosis in lower-grade gioma by modulating immunity, matrix, stemness, and metabolism. Front Mol Biosci 2022; 9:1027236. [PMID: 36589241 PMCID: PMC9800986 DOI: 10.3389/fmolb.2022.1027236] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2022] [Accepted: 11/28/2022] [Indexed: 12/23/2022] Open
Abstract
Background: The CCN family of stromal proteins is involved in the regulation of many important biological functions. However, the role of dysregulated CCN proteins in lower-grade glioma (LGG) remain less understand. Methods: The clinical significance of the CCN proteins was explored based on RNA-seq profiles from multiple cohorts. A CCNScore was constructed using LASSO regression analysis. The PanCanAtlas data and MEXPRESS database were employed to elucidate molecular underpinnings. Results: The expression of CCN4 was associated with poor prognosis in LGG. The CCNScore (CCN1 = 0.06, CCN4 = 0.86) showed implication in prognosis prediction, subtype assessment and therapy selection. The gene mutation pattern of the high-CCNScore group was similar with glioblastoma, including EGFR, PTEN, and NF1 mutation frequently. Besides, the high-CCNScore group was comprised of samples mainly classic-like and mesenchymal-like, had lower methylation levels, higher stemness, higher inflammation, higher levels of extracellular matrix remodel and dysfunction of metabolic pathways. On the other hand, the low-CCNScore group consisted mainly of IDH-mutation LGG, and was characterized by TP53, CIC, and ATRX gene mutations, hyper-methylation status, lower stemness, lower proliferation, immune quietness and low extracellular matrix stiffness. Conclusion: In summary, these results outlined the role of CCN family in LGG and provided a potential and promising therapeutic target.
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Affiliation(s)
- Zhihui Liu
- Cancer Center, Department of Neurosurgery, Zhejiang Provincial People’s Hospital, Affiliated People’s Hospital, Hangzhou Medical College, Hangzhou, Zhejiang, China
| | - Jiasheng Wu
- Cancer Center, Department of Neurosurgery, Zhejiang Provincial People’s Hospital, Affiliated People’s Hospital, Hangzhou Medical College, Hangzhou, Zhejiang, China
| | - Hang Ji
- Department of Neurosurgery, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Hongtao Zhao
- Cancer Center, Department of Neurosurgery, Zhejiang Provincial People’s Hospital, Affiliated People’s Hospital, Hangzhou Medical College, Hangzhou, Zhejiang, China
| | - Fang Wang
- Cancer Center, Department of Neurosurgery, Zhejiang Provincial People’s Hospital, Affiliated People’s Hospital, Hangzhou Medical College, Hangzhou, Zhejiang, China
| | - Jiawei Dong
- Cancer Center, Department of Neurosurgery, Zhejiang Provincial People’s Hospital, Affiliated People’s Hospital, Hangzhou Medical College, Hangzhou, Zhejiang, China
| | - Jiheng Zhang
- Cancer Center, Department of Neurosurgery, Zhejiang Provincial People’s Hospital, Affiliated People’s Hospital, Hangzhou Medical College, Hangzhou, Zhejiang, China
| | - Nan Wang
- Cancer Center, Department of Neurosurgery, Zhejiang Provincial People’s Hospital, Affiliated People’s Hospital, Hangzhou Medical College, Hangzhou, Zhejiang, China
| | - Xiuwei Yan
- Cancer Center, Department of Neurosurgery, Zhejiang Provincial People’s Hospital, Affiliated People’s Hospital, Hangzhou Medical College, Hangzhou, Zhejiang, China,*Correspondence: Xiuwei Yan, ; Kaikai Wang, ; Shaoshan Hu,
| | - Kaikai Wang
- Department of Neurosurgery, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Zhejiang, Hangzhou, China,Key Laboratory of Precise Treatment and Clinical Translational Research of Neurological Diseases, Hangzhou, Zhejiang, China,*Correspondence: Xiuwei Yan, ; Kaikai Wang, ; Shaoshan Hu,
| | - Shaoshan Hu
- Cancer Center, Department of Neurosurgery, Zhejiang Provincial People’s Hospital, Affiliated People’s Hospital, Hangzhou Medical College, Hangzhou, Zhejiang, China,*Correspondence: Xiuwei Yan, ; Kaikai Wang, ; Shaoshan Hu,
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28
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Li H, He J, Li M, Li K, Pu X, Guo Y. Immune landscape-based machine-learning-assisted subclassification, prognosis, and immunotherapy prediction for glioblastoma. Front Immunol 2022; 13:1027631. [PMID: 36532035 PMCID: PMC9751405 DOI: 10.3389/fimmu.2022.1027631] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2022] [Accepted: 11/15/2022] [Indexed: 12/04/2022] Open
Abstract
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.
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Singh M, Raghav A, Gautam KA. Role of the circulatory interleukin-6 in the pathogenesis of gliomas: A systematic review. World J Methodol 2022; 12:428-437. [PMID: 36186749 PMCID: PMC9516551 DOI: 10.5662/wjm.v12.i5.428] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/13/2021] [Revised: 04/01/2022] [Accepted: 07/25/2022] [Indexed: 02/08/2023] Open
Abstract
BACKGROUND Glioma is the most common primary tumor in the brain originating from glial cells. In spite of extensive research, the overall survival rate is not enhanced. A number of published articles observed differentially circulating levels of cytokines in glioma. Interleukin-6 (IL-6) protein coded by IL-6 gene is regulated by the immune system and it has been found to have a significant role in progression and apoptosis resistance of glioma.
AIM To review the role of circulatory IL-6 in the development and progression of glioma and its utility as a biomarker.
METHODS Preferred Reporting Items for Systematic Reviews and Meta-analysis (PRISMA) guidelines were applied to filter the relevant studies based on inclusion and exclusion criteria. We used a combination of keywords and the Reference Citation Analysis (RCA) tool to search the potential studies and performed data extraction from selected studies.
RESULTS The published results were inconsistent; however, most studies showed a significantly higher IL-6 level in glioma cases as compared to controls. Comparative IL-6 level among the different grades of glioma showed a higher level with low-grade gliomas and lower level with high-grade gliomas.
CONCLUSION IL-6 level significantly differed between cases and controls, and among different cancer stages, which shows its potential as a diagnostic and prognostic marker.
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Affiliation(s)
- Manish Singh
- Department of Neurosurgery, GSVM Medical College, Kanpur 208001, India
| | - Alok Raghav
- Department of Neurosurgery, GSVM Medical College, Kanpur 208001, India
| | - Kirti Amresh Gautam
- Department of Basic and Applied Science, GD Goenka University, Gurugram 122103, Haryana, India
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30
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Idoate Gastearena MA, López-Janeiro Á, Lecumberri Aznarez A, Arana-Iñiguez I, Guillén-Grima F. A Quantitative Digital Analysis of Tissue Immune Components Reveals an Immunosuppressive and Anergic Immune Response with Relevant Prognostic Significance in Glioblastoma. Biomedicines 2022; 10:biomedicines10071753. [PMID: 35885058 PMCID: PMC9313250 DOI: 10.3390/biomedicines10071753] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2022] [Revised: 07/10/2022] [Accepted: 07/15/2022] [Indexed: 11/16/2022] Open
Abstract
Objectives: Immunostimulatory therapies using immune checkpoint blockers show clinical activity in a subset of glioblastoma (GBM) patients. Several inhibitory mechanisms play a relevant role in the immune response to GBM. With the objective of analyzing the tumor immune microenvironment and its clinical significance, we quantified several relevant immune biomarkers. Design: We studied 76 primary (non-recurrent) GBMs with sufficient clinical follow-up, including a subgroup of patients treated with a dendritic cell vaccine. The IDH-mutation, EGFR-amplification, and MGMT methylation statuses were determined. Several relevant immune biomarkers, including CD163, CD8, PD1, and PDL1, were quantified in representative selected areas by digital image analysis and semiquantitative evaluation. The percentage of each immune expression was calculated with respect to the total number of tumor cells. Results: All GBMs were wild-type IDH, with a subgroup of classical GBMs according to the EGFR amplification (44%). Morphologically, CD163 immunostained microglia and intratumor clusters of macrophages were observed. A significant direct correlation was found between the expression of CD8 and the mechanisms of lymphocyte immunosuppression, in such a way that higher values of CD8 were directly associated with higher values of CD163 (p < 0.001), PDL1 (0.026), and PD1 (0.007). In a multivariate analysis, high expressions of CD8+ (HR = 2.05, 95%CI (1.02−4.13), p = 0.034) and CD163+ cells (HR 2.50, 95%CI (1.29−4.85), p = 0.007), were associated with shorter survival durations. The expression of immune biomarkers was higher in the non-classical (non-EGFR amplified tumors) GBMs. Other relevant prognostic factors were age, receipt of the dendritic cell vaccine, and MGMT methylation status. Conclusions: In accordance with the inverse correlation between CD8 and survival and the direct correlation between effector cells and CD163 macrophages and immune-checkpoint expression, we postulate that CD8 infiltration could be placed in a state of anergy or lymphocytic inefficient activity. Furthermore, the significant inverse correlation between CD163 tissue concentration and survival explains the relevance of this type of immune cell when creating a strong immunosuppressive environment. This information may potentially be used to support the selection of patients for immunotherapy.
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Affiliation(s)
- Miguel A. Idoate Gastearena
- Pathology Department, Clinica Universidad de Navarra and School of Medicine, University of Navarra, 31008 Pamplona, Spain; (Á.L.-J.); (A.L.A.); (I.A.-I.)
- Pathology Department, Virgen Macarena University Hospital and School of Medicine, University of Seville, 41009 Seville, Spain
- Correspondence: ; Tel.: +34-660460714
| | - Álvaro López-Janeiro
- Pathology Department, Clinica Universidad de Navarra and School of Medicine, University of Navarra, 31008 Pamplona, Spain; (Á.L.-J.); (A.L.A.); (I.A.-I.)
| | - Arturo Lecumberri Aznarez
- Pathology Department, Clinica Universidad de Navarra and School of Medicine, University of Navarra, 31008 Pamplona, Spain; (Á.L.-J.); (A.L.A.); (I.A.-I.)
| | - Iñigo Arana-Iñiguez
- Pathology Department, Clinica Universidad de Navarra and School of Medicine, University of Navarra, 31008 Pamplona, Spain; (Á.L.-J.); (A.L.A.); (I.A.-I.)
| | - Francisco Guillén-Grima
- Department of Preventive Medicine, Clinica Universidad de Navarra, University of Navarra, 31008 Pamplona, Spain;
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Yu ZL, Liu JY, Chen G. Small extracellular vesicle PD-L1 in cancer: the knowns and unknowns. NPJ Precis Oncol 2022; 6:42. [PMID: 35729210 PMCID: PMC9213536 DOI: 10.1038/s41698-022-00287-3] [Citation(s) in RCA: 23] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2021] [Accepted: 05/12/2022] [Indexed: 12/24/2022] Open
Abstract
According to the conventional wisdom, programmed death protein 1 ligand (PD-L1)-mediated immunosuppression was based on the physical contact between tumor cells and T cells in the tumor microenvironment. Recent studies demonstrated that PD-L1 was also highly expressed on the surface of tumor cell-derived small extracellular vesicles (sEVs). PD-L1 on sEVs, which could also directly bind to PD-1 on T cells, has a vital function in immunosuppression and immunotherapy resistance. Due to the heterogeneity and dynamic changes of PD-L1 expression on tumor cells, developing sEV PD-L1 as a predictive biomarker for the clinical responses to immunotherapy could be an attractive option. In this review, we summarized and discussed the latest researches and advancements on sEV PD-L1, including the biogenesis and secretion mechanisms, isolation and detection strategies, as well as the biological functions of sEV PD-L1. In the meantime, we highlighted the application potential of sEV PD-L1 as diagnostic and prognostic markers in tumor, especially for predicting the clinical responses to anti-PD-1/PD-L1 immunotherapies. In particular, with the gradual deepening of the studies, challenges and problems regarding the further understanding and application of sEV PD-L1 have begun to emerge. Based on the current research status, we summarized the potential challenges and possible solutions, and prospected several key directions for future studies of sEV PD-L1. Collectively, by highlighting the important knowns and unknowns of sEV PD-L1, our present review would help to light the way forward for the field of sEV PD-L1 and to avoid unnecessary blindness and detours.
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Affiliation(s)
- Zi-Li Yu
- The State Key Laboratory Breeding Base of Basic Science of Stomatology (Hubei-MOST) & Key Laboratory of Oral Biomedicine Ministry of Education, School and Hospital of Stomatology, Wuhan University, Wuhan, 430079, China.,Department of Oral and Maxillofacial Surgery, School and Hospital of Stomatology, Wuhan University, Wuhan, 430079, China
| | - Jin-Yuan Liu
- The State Key Laboratory Breeding Base of Basic Science of Stomatology (Hubei-MOST) & Key Laboratory of Oral Biomedicine Ministry of Education, School and Hospital of Stomatology, Wuhan University, Wuhan, 430079, China
| | - Gang Chen
- The State Key Laboratory Breeding Base of Basic Science of Stomatology (Hubei-MOST) & Key Laboratory of Oral Biomedicine Ministry of Education, School and Hospital of Stomatology, Wuhan University, Wuhan, 430079, China. .,Department of Oral and Maxillofacial Surgery, School and Hospital of Stomatology, Wuhan University, Wuhan, 430079, China. .,Frontier Science Center for Immunology and Metabolism, Wuhan University, Wuhan, 430071, China.
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Larkin CJ, Arrieta VA, Najem H, Li G, Zhang P, Miska J, Chen P, James CD, Sonabend AM, Heimberger AB. Myeloid Cell Classification and Therapeutic Opportunities Within the Glioblastoma Tumor Microenvironment in the Single Cell-Omics Era. Front Immunol 2022; 13:907605. [PMID: 35784281 PMCID: PMC9244707 DOI: 10.3389/fimmu.2022.907605] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2022] [Accepted: 05/18/2022] [Indexed: 11/13/2022] Open
Abstract
The glioma tumor microenvironment (TME) is complex and heterogeneous, and multiple emerging and current technologies are being utilized for an improved comprehension and understanding of these tumors. Single cell analysis techniques such as single cell genomic and transcriptomic sequencing analysis are on the rise and play an important role in elucidating the glioma TME. These large datasets will prove useful for patient tumor characterization, including immune configuration that will ultimately influence therapeutic choices and especially immune therapies. In this review we discuss the advantages and drawbacks of these techniques while debating their role in the domain of glioma-infiltrating myeloid cells characterization and function.
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Affiliation(s)
- Collin J. Larkin
- Department of Neurological Surgery, Northwestern University Feinberg School of Medicine, Chicago, IL, United States
| | - Víctor A. Arrieta
- Department of Neurological Surgery, Northwestern University Feinberg School of Medicine, Chicago, IL, United States
- Lou and Jean Malnati Brain Tumor Institute of the Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, IL, United States
- Programa de Estudios Combinados en Medicina (PECEM), Facultad de Medicina, Universidad Nacional Autónoma de México, Mexico City, Mexico
| | - Hinda Najem
- Department of Neurological Surgery, Northwestern University Feinberg School of Medicine, Chicago, IL, United States
- Lou and Jean Malnati Brain Tumor Institute of the Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, IL, United States
| | - Gongbo Li
- Department of Neurological Surgery, Northwestern University Feinberg School of Medicine, Chicago, IL, United States
- Lou and Jean Malnati Brain Tumor Institute of the Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, IL, United States
| | - Peng Zhang
- Department of Neurological Surgery, Northwestern University Feinberg School of Medicine, Chicago, IL, United States
- Lou and Jean Malnati Brain Tumor Institute of the Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, IL, United States
| | - Jason Miska
- Department of Neurological Surgery, Northwestern University Feinberg School of Medicine, Chicago, IL, United States
- Lou and Jean Malnati Brain Tumor Institute of the Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, IL, United States
| | - Peiwen Chen
- Department of Neurological Surgery, Northwestern University Feinberg School of Medicine, Chicago, IL, United States
- Lou and Jean Malnati Brain Tumor Institute of the Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, IL, United States
| | - Charles David James
- Department of Neurological Surgery, Northwestern University Feinberg School of Medicine, Chicago, IL, United States
- Lou and Jean Malnati Brain Tumor Institute of the Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, IL, United States
| | - Adam M. Sonabend
- Department of Neurological Surgery, Northwestern University Feinberg School of Medicine, Chicago, IL, United States
- Lou and Jean Malnati Brain Tumor Institute of the Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, IL, United States
| | - Amy B. Heimberger
- Department of Neurological Surgery, Northwestern University Feinberg School of Medicine, Chicago, IL, United States
- Lou and Jean Malnati Brain Tumor Institute of the Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, IL, United States
- *Correspondence: Amy B. Heimberger,
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Translational landscape of glioblastoma immunotherapy for physicians: guiding clinical practice with basic scientific evidence. J Hematol Oncol 2022; 15:80. [PMID: 35690784 PMCID: PMC9188021 DOI: 10.1186/s13045-022-01298-0] [Citation(s) in RCA: 45] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2022] [Accepted: 05/10/2022] [Indexed: 02/06/2023] Open
Abstract
Despite recent advances in cancer therapeutics, glioblastoma (GBM) remains one of the most difficult cancers to treat in both the primary and recurrent settings. GBM presents a unique therapeutic challenge given the immune-privileged environment of the brain and the aggressive nature of the disease. Furthermore, it can change phenotypes throughout the course of disease—switching between mesenchymal, neural, and classic gene signatures, each with specific markers and mechanisms of resistance. Recent advancements in the field of immunotherapy—which utilizes strategies to reenergize or alter the immune system to target cancer—have shown striking results in patients with many types of malignancy. Immune checkpoint inhibitors, adoptive cellular therapy, cellular and peptide vaccines, and other technologies provide clinicians with a vast array of tools to design highly individualized treatment and potential for combination strategies. There are currently over 80 active clinical trials evaluating immunotherapies for GBM, often in combination with standard secondary treatment options including re-resection and anti-angiogenic agents, such as bevacizumab. This review will provide a clinically focused overview of the immune environment present in GBM, which is frequently immunosuppressive and characterized by M2 macrophages, T cell exhaustion, enhanced transforming growth factor-β signaling, and others. We will also outline existing immunotherapeutic strategies, with a special focus on immune checkpoint inhibitors, chimeric antigen receptor therapy, and dendritic cell vaccines. Finally, we will summarize key discoveries in the field and discuss currently active clinical trials, including combination strategies, burgeoning technology like nucleic acid and nanoparticle therapy, and novel anticancer vaccines. This review aims to provide the most updated summary of the field of immunotherapy for GBM and offer both historical perspective and future directions to help inform clinical practice.
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Lou X, Gao H, Xu X, Ye Z, Zhang W, Wang F, Chen J, Zhang Y, Chen X, Qin Y, Yu X, Ji S. The Interplay of Four Main Pathways Recomposes Immune Landscape in Primary and Metastatic Gastroenteropancreatic Neuroendocrine Tumors. Front Oncol 2022; 12:808448. [PMID: 35664743 PMCID: PMC9158120 DOI: 10.3389/fonc.2022.808448] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2021] [Accepted: 04/08/2022] [Indexed: 11/29/2022] Open
Abstract
BACKGROUND The four major pathways in gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs) including chromatin remodeling, DNA damage repair, activation of mTOR signaling, and telomere maintenance were mediated by some critical molecules and constituted critical processes of regulation in cancer-causing processes. However, the interplay and potential role of these pathway-related molecules in the tumor microenvironment of the primary and metastatic site remained unknown. METHODS We systematically evaluated the mRNA expression of 34 molecules associated with the four pathways in 227 GEP-NEN samples from 5 datasets. We assigned the samples into two expression patterns of pathway-related molecules by an unsupervised clustering method. Subsequently, we explored the specific cell-related molecules, especially immune and stromal cells using the WGCNA method, based on differentially expressed genes (DEGs) responsible for the different patterns of pathway-related molecules, which provided a new method to qualify the pathway-related subtypes of individual tumors, then the PC_Score and PI_Score scoring systems were also constructed using obtained specific cell-related molecules. Furthermore, we performed the association of pathway-related subtypes with characteristics of immune landscape in primary and metastatic GEP-NENs. RESULTS We demonstrated that the specific pathway-related molecules (SMARCA4, MLH1, TSC1, ATRX, and ATR) were associated with cytolytic activity. Then we identified the two distinct patterns of pathway-related molecules, which were characteristic with a significantly distinct immune landscape. Using WGCNA, we also identified the fibroblast-related molecules, including ASPN, COL10A1, COL3A1, EDNRA, MYL9, PRELP, RAB31, SPARC, and THBS2, and immune-related molecules including CASP1, CCL5, CTSS, CYBRD1, PMP22, and TFEC. Based on these specific markers, we identified four distinct pathway-related subtypes, characterized by immune and fibrotic enriched (I/FE), immune enriched (IE), fibrotic enriched (FE), and immune and fibrotic desert (I/FD), of which I/FE was characteristic with the highest PC_Score and PI_Score whereas I/FD presents the opposite trend. I/FE was positively correlated with immune landscape of T-cell activation and immunosuppression. Furthermore, the I/FE marked GEP-NENs with increased immune activation scores (T-cell costimulation, MHC I presentation, and APC costimulation). Importantly, the four distinct pathway-related subtypes were not conserved in different tumor sites, because I/FE was lacking in the liver metastatic site even though IE, FE, and I/FD also could be observed in the metastatic site. CONCLUSIONS This study was the first to perform a comprehensive analysis of the four major pathways in GEP-NENs. We demonstrated the potential function of these pathway-related molecules in immune landscapes. Our findings indicated that the primary and metastatic GEP-NENs had distinct antitumor phenotypes. This work highlighted the interplay and potential clinical utility of these pathway-related molecules in GEP-NENs.
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Affiliation(s)
- Xin Lou
- Center for Neuroendocrine Tumors, Fudan University Shanghai Cancer Center, Shanghai, China
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
- Shanghai Pancreatic Cancer Institute, Shanghai, China
- Pancreatic Cancer Institute, Fudan University, Shanghai, China
| | - Heli Gao
- Center for Neuroendocrine Tumors, Fudan University Shanghai Cancer Center, Shanghai, China
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
- Shanghai Pancreatic Cancer Institute, Shanghai, China
- Pancreatic Cancer Institute, Fudan University, Shanghai, China
| | - Xiaowu Xu
- Center for Neuroendocrine Tumors, Fudan University Shanghai Cancer Center, Shanghai, China
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
- Shanghai Pancreatic Cancer Institute, Shanghai, China
- Pancreatic Cancer Institute, Fudan University, Shanghai, China
| | - Zeng Ye
- Center for Neuroendocrine Tumors, Fudan University Shanghai Cancer Center, Shanghai, China
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
- Shanghai Pancreatic Cancer Institute, Shanghai, China
- Pancreatic Cancer Institute, Fudan University, Shanghai, China
| | - Wuhu Zhang
- Center for Neuroendocrine Tumors, Fudan University Shanghai Cancer Center, Shanghai, China
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
- Shanghai Pancreatic Cancer Institute, Shanghai, China
- Pancreatic Cancer Institute, Fudan University, Shanghai, China
| | - Fei Wang
- Center for Neuroendocrine Tumors, Fudan University Shanghai Cancer Center, Shanghai, China
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
- Shanghai Pancreatic Cancer Institute, Shanghai, China
- Pancreatic Cancer Institute, Fudan University, Shanghai, China
| | - Jie Chen
- Center for Neuroendocrine Tumors, Fudan University Shanghai Cancer Center, Shanghai, China
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
- Shanghai Pancreatic Cancer Institute, Shanghai, China
- Pancreatic Cancer Institute, Fudan University, Shanghai, China
| | - Yue Zhang
- Department of Hepatopancreatobiliary Surgery, the Third Affiliated Hospital of Soochow University, Changzhou, China
| | - Xuemin Chen
- Department of Hepatopancreatobiliary Surgery, the Third Affiliated Hospital of Soochow University, Changzhou, China
| | - Yi Qin
- Center for Neuroendocrine Tumors, Fudan University Shanghai Cancer Center, Shanghai, China
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
- Shanghai Pancreatic Cancer Institute, Shanghai, China
- Pancreatic Cancer Institute, Fudan University, Shanghai, China
| | - Xianjun Yu
- Center for Neuroendocrine Tumors, Fudan University Shanghai Cancer Center, Shanghai, China
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
- Shanghai Pancreatic Cancer Institute, Shanghai, China
- Pancreatic Cancer Institute, Fudan University, Shanghai, China
| | - Shunrong Ji
- Center for Neuroendocrine Tumors, Fudan University Shanghai Cancer Center, Shanghai, China
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
- Shanghai Pancreatic Cancer Institute, Shanghai, China
- Pancreatic Cancer Institute, Fudan University, Shanghai, China
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Shafi O, Siddiqui G. Tracing the origins of glioblastoma by investigating the role of gliogenic and related neurogenic genes/signaling pathways in GBM development: a systematic review. World J Surg Oncol 2022; 20:146. [PMID: 35538578 PMCID: PMC9087910 DOI: 10.1186/s12957-022-02602-5] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2022] [Accepted: 04/15/2022] [Indexed: 02/16/2023] Open
Abstract
Background Glioblastoma is one of the most aggressive tumors. The etiology and the factors determining its onset are not yet entirely known. This study investigates the origins of GBM, and for this purpose, it focuses primarily on developmental gliogenic processes. It also focuses on the impact of the related neurogenic developmental processes in glioblastoma oncogenesis. It also addresses why glial cells are at more risk of tumor development compared to neurons. Methods Databases including PubMed, MEDLINE, and Google Scholar were searched for published articles without any date restrictions, involving glioblastoma, gliogenesis, neurogenesis, stemness, neural stem cells, gliogenic signaling and pathways, neurogenic signaling and pathways, and astrocytogenic genes. Results The origin of GBM is dependent on dysregulation in multiple genes and pathways that accumulatively converge the cells towards oncogenesis. There are multiple layers of steps in glioblastoma oncogenesis including the failure of cell fate-specific genes to keep the cells differentiated in their specific cell types such as p300, BMP, HOPX, and NRSF/REST. There are genes and signaling pathways that are involved in differentiation and also contribute to GBM such as FGFR3, JAK-STAT, and hey1. The genes that contribute to differentiation processes but also contribute to stemness in GBM include notch, Sox9, Sox4, c-myc gene overrides p300, and then GFAP, leading to upregulation of nestin, SHH, NF-κB, and others. GBM mutations pathologically impact the cell circuitry such as the interaction between Sox2 and JAK-STAT pathway, resulting in GBM development and progression. Conclusion Glioblastoma originates when the gene expression of key gliogenic genes and signaling pathways become dysregulated. This study identifies key gliogenic genes having the ability to control oncogenesis in glioblastoma cells, including p300, BMP, PAX6, HOPX, NRSF/REST, LIF, and TGF beta. It also identifies key neurogenic genes having the ability to control oncogenesis including PAX6, neurogenins including Ngn1, NeuroD1, NeuroD4, Numb, NKX6-1 Ebf, Myt1, and ASCL1. This study also postulates how aging contributes to the onset of glioblastoma by dysregulating the gene expression of NF-κB, REST/NRSF, ERK, AKT, EGFR, and others.
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Affiliation(s)
- Ovais Shafi
- Sindh Medical College - Jinnah Sindh Medical University / Dow University of Health Sciences, Karachi, Pakistan.
| | - Ghazia Siddiqui
- Sindh Medical College - Jinnah Sindh Medical University / Dow University of Health Sciences, Karachi, Pakistan
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Bockmayr M, Harnisch K, Pohl LC, Schweizer L, Mohme T, Körner M, Alawi M, Suwala AK, Dorostkar MM, Monoranu CM, Hasselblatt M, Wefers AK, Capper D, Hench J, Frank S, Richardson TE, Tran I, Liu E, Snuderl M, Engertsberger L, Benesch M, von Deimling A, Obrecht D, Mynarek M, Rutkowski S, Glatzel M, Neumann JE, Schüller U. Comprehensive profiling of myxopapillary ependymomas identifies a distinct molecular subtype with relapsing disease. Neuro Oncol 2022; 24:1689-1699. [PMID: 35380708 PMCID: PMC9527524 DOI: 10.1093/neuonc/noac088] [Citation(s) in RCA: 22] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
Abstract
BACKGROUND Myxopapillary ependymoma (MPE) is a heterogeneous disease regarding histopathology and outcome. The underlying molecular biology is poorly understood, and markers that reliably predict the patients' clinical course are unknown. METHODS We assembled a cohort of 185 tumors classified as MPE based on DNA methylation. Methylation patterns, copy number profiles, and MGMT promoter methylation were analyzed for all tumors, 106 tumors were evaluated histomorphologically, and RNA sequencing was performed for 37 cases. Based on methylation profiling, we defined two subtypes MPE-A and MPEB, and explored associations with epidemiological, clinical, pathological, and molecular characteristics of these tumors. RESULTS MPE-A occurred at a median age of 27 years and were enriched with tumors demonstrating papillary morphology and MGMT promoter hypermethylation. Half of these tumors could not be totally resected, and 85% relapsed within 10 years. Copy number alterations were more common in MPE-A. RNA sequencing revealed an enrichment for extracellular matrix and immune system-related signatures in MPE-A. MPE-B occurred at a median age of 45 years and included many tumors with a histological diagnosis of WHO grade II and tanycytic morphology. Patients within this subtype had a significantly better outcome with a relapse rate of 33% in 10 years (p=3.4e-06). CONCLUSIONS We unraveled the morphological and clinical heterogeneity of MPE by identifying two molecularly distinct subtypes. These subtypes significantly differed in progression-free survival and will likely need different protocols for surveillance and treatment.
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Affiliation(s)
- Michael Bockmayr
- Department of Pediatric Hematology and Oncology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.,Research Institute Children's Cancer Center Hamburg, Hamburg, Germany.,Mildred Scheel Cancer Career Center HaTriCS4, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.,Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Institute of Pathology, Berlin, Germany
| | - Kim Harnisch
- Institute of Neuropathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.,Institute for Neuropathology, University Hospital of Zurich, Switzerland
| | - Lara C Pohl
- Department of Pediatric Hematology and Oncology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.,Research Institute Children's Cancer Center Hamburg, Hamburg, Germany
| | - Leonille Schweizer
- Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Department of Neuropathology, Berlin, Germany.,German Cancer Consortium (DKTK), Partner Site Berlin, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Theresa Mohme
- Department of Neurosurgery, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Meik Körner
- Department of Pediatric Hematology and Oncology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.,Research Institute Children's Cancer Center Hamburg, Hamburg, Germany
| | - Malik Alawi
- Bioinformatics Core, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Abigail K Suwala
- Department of Neuropathology, Institute of Pathology, University of Heidelberg, Germany.,Clinical Cooperation Unit Neuropathology, German Consortium for Translational Cancer Research (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany.,Department of Neurological Surgery, UCSF, San Francisco, CA, USA
| | - Mario M Dorostkar
- Center for Neuropathology, Ludwig-Maximilians-University, Munich, Germany German Center for Neurodegenerative Diseases, Munich, Germany
| | - Camelia M Monoranu
- Department of Neuropathology, Institute of Pathology, University of Würzburg, Würzburg, Germany Institute of Neuropathology, University Hospital Münster, Münster, Germany
| | - Martin Hasselblatt
- Department of Neuropathology, Institute of Pathology, University of Würzburg, Würzburg, Germany Institute of Neuropathology, University Hospital Münster, Münster, Germany
| | - Annika K Wefers
- Mildred Scheel Cancer Career Center HaTriCS4, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.,Institute of Neuropathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - David Capper
- Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Department of Neuropathology, Berlin, Germany.,German Cancer Consortium (DKTK), Partner Site Berlin, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Jürgen Hench
- Division of Neuropathology, Institute of Medical Genetics and Pathology, University of Basel, Basel, Switzerland
| | - Stephan Frank
- Division of Neuropathology, Institute of Medical Genetics and Pathology, University of Basel, Basel, Switzerland
| | - Timothy E Richardson
- Department of Pathology and Laboratory Medicine, Glenn Biggs Institute for Alzheimer's & Neurodegenerative Diseases, UT Health San Antonio, TX, USA
| | - Ivy Tran
- Department of Pathology, NYU Langone Health, New York City, NY, USA
| | - Elisa Liu
- Department of Pathology, NYU Langone Health, New York City, NY, USA
| | - Matija Snuderl
- Department of Pathology, NYU Langone Health, New York City, NY, USA
| | - Lara Engertsberger
- Division of Pediatric Hematology and Oncology, Department of Pediatrics and Adolescent Medicine, Medical University of Graz, Austria
| | - Martin Benesch
- Division of Pediatric Hematology and Oncology, Department of Pediatrics and Adolescent Medicine, Medical University of Graz, Austria
| | - Andreas von Deimling
- Department of Neuropathology, Institute of Pathology, University of Heidelberg, Germany
| | - Denise Obrecht
- Department of Pediatric Hematology and Oncology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Martin Mynarek
- Department of Pediatric Hematology and Oncology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.,Mildred Scheel Cancer Career Center HaTriCS4, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Stefan Rutkowski
- Department of Pediatric Hematology and Oncology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Markus Glatzel
- Institute of Neuropathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Julia E Neumann
- Institute of Neuropathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.,Center for Molecular Neurobiology Hamburg, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Ulrich Schüller
- Department of Pediatric Hematology and Oncology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.,Research Institute Children's Cancer Center Hamburg, Hamburg, Germany.,Institute of Neuropathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
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Markwell SM, Ross JL, Olson CL, Brat DJ. Necrotic reshaping of the glioma microenvironment drives disease progression. Acta Neuropathol 2022; 143:291-310. [PMID: 35039931 DOI: 10.1007/s00401-021-02401-4] [Citation(s) in RCA: 39] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2021] [Revised: 12/20/2021] [Accepted: 12/21/2021] [Indexed: 12/13/2022]
Abstract
Glioblastoma is the most common primary brain tumor and has a dismal prognosis. The development of central necrosis represents a tipping point in the evolution of these tumors that foreshadows aggressive expansion, swiftly leading to mortality. The onset of necrosis, severe hypoxia and associated radial glioma expansion correlates with dramatic tumor microenvironment (TME) alterations that accelerate tumor growth. In the past, most have concluded that hypoxia and necrosis must arise due to "cancer outgrowing its blood supply" when rapid tumor growth outpaces metabolic supply, leading to diffusion-limited hypoxia. However, growing evidence suggests that microscopic intravascular thrombosis driven by the neoplastic overexpression of pro-coagulants attenuates glioma blood supply (perfusion-limited hypoxia), leading to TME restructuring that includes breakdown of the blood-brain barrier, immunosuppressive immune cell accumulation, microvascular hyperproliferation, glioma stem cell enrichment and tumor cell migration outward. Cumulatively, these adaptations result in rapid tumor expansion, resistance to therapeutic interventions and clinical progression. To inform future translational investigations, the complex interplay among environmental cues and myriad cell types that contribute to this aggressive phenotype requires better understanding. This review focuses on contributions from intratumoral thrombosis, the effects of hypoxia and necrosis, the adaptive and innate immune responses, and the current state of targeted therapeutic interventions.
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Affiliation(s)
- Steven M Markwell
- Department of Pathology, Northwestern Medicine Malnati Brain Tumor Institute of the Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, 303 E. Chicago Ave. Ward 3-140, Chicago, IL, USA
| | - James L Ross
- Department of Microbiology and Immunology, Emory University, Atlanta, GA, USA
| | - Cheryl L Olson
- Department of Pathology, Northwestern Medicine Malnati Brain Tumor Institute of the Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, 303 E. Chicago Ave. Ward 3-140, Chicago, IL, USA
| | - Daniel J Brat
- Department of Pathology, Northwestern Medicine Malnati Brain Tumor Institute of the Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, 303 E. Chicago Ave. Ward 3-140, Chicago, IL, USA.
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Mehani B, Asanigari S, Chung HJ, Dazelle K, Singh A, Hannenhalli S, Aldape K. Immune cell gene expression signatures in diffuse glioma are associated with IDH mutation status, patient outcome and malignant cell state, and highlight the importance of specific cell subsets in glioma biology. Acta Neuropathol Commun 2022; 10:19. [PMID: 35144680 PMCID: PMC8830123 DOI: 10.1186/s40478-022-01323-w] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2021] [Accepted: 01/27/2022] [Indexed: 12/17/2022] Open
Abstract
The tumor micro-environment (TME) plays an important role in various cancers, including gliomas. We estimated immune cell type-specific gene expression profiles in 3 large clinically annotated glioma datasets using CIBERSORTx and LM22/LM10 blood-based immune signatures and found that the proportions and estimated gene expression patterns of specific immune cells significantly varied according to IDH mutation status. When IDH-WT and IDH-MUT tumors were considered separately, cluster-of-cluster analyses of immune cell gene expression identified groups with distinct survival outcomes. We confirmed and extended these findings by applying a signature matrix derived from single-cell RNA-sequencing data derived from 19 glioma tumor samples to the bulk profiling data, validating findings from the LM22/LM10 results. To link immune cell signatures with outcomes in checkpoint therapy, we then showed a significant association of monocytic lineage cell gene expression clusters with patient survival and with mesenchymal gene expression scores. Integrating immune cell-based gene expression with previously described malignant cell states in glioma demonstrated that macrophage M0 abundance significantly correlated with mesenchymal state in IDH-WT gliomas, with evidence of a previously implicated role of the Oncostatin-M receptor and macrophages in the mesenchymal state. Among IDH-WT tumors that were enriched for the mesenchymal cell state, the estimated M0 macrophage expression signature coordinately also trended to a mesenchymal signature. We also examined IDH-MUT tumors stratified by 1p/19q status, showing that a mesenchymal gene expression signature the M0 macrophage fraction was enriched in IDH-MUT, non-codeleted tumors. Overall, these results highlight the biological and clinical significance of the immune cell environment related to IDH mutation status, patient prognosis and the mesenchymal state in diffuse gliomas.
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Vimalathas G, Kristensen BW. Expression, prognostic significance and therapeutic implications of PD-L1 in gliomas. Neuropathol Appl Neurobiol 2022; 48:e12767. [PMID: 34533233 PMCID: PMC9298327 DOI: 10.1111/nan.12767] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2020] [Revised: 08/27/2021] [Accepted: 09/14/2021] [Indexed: 12/19/2022]
Abstract
The advent of checkpoint immunotherapy, particularly with programmed death-1 (PD-1) and programmed death-ligand 1 (PD-L1) inhibitors, has provided ground-breaking results in several advanced cancers. Substantial efforts are being made to extend these promising therapies to other refractory cancers such as gliomas, especially glioblastoma, which represents the most frequent and malignant glioma and carries an exceptionally grim prognosis. Thus, there is a need for new therapeutic strategies with related biomarkers. Gliomas have a profoundly immunosuppressive tumour micro-environment and evade immunological destruction by several mechanisms, one being the expression of inhibitory immune checkpoint molecules such as PD-L1. PD-L1 is recognised as an important therapeutic target and its expression has been shown to hold prognostic value in different cancers. Several clinical trials have been launched and some already completed, but PD-1/PD-L1 inhibitors have yet to show convincing clinical efficacy in gliomas. Part of the explanation may reside in the vast molecular heterogeneity of gliomas and a complex interplay within the tumour micro-environment. In parallel, critical knowledge about PD-L1 expression is beginning to accumulate including knowledge on expression levels, testing methodology, co-expression with other checkpoint molecules and prognostic and predictive value. This article reviews these aspects and points out areas where biomarker research is needed to develop more successful checkpoint-related therapeutic strategies in gliomas.
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Affiliation(s)
| | - Bjarne Winther Kristensen
- Department of PathologyOdense University HospitalOdenseDenmark
- Department of Pathology, RigshospitaletCopenhagen University HospitalCopenhagenDenmark
- Department of Clinical Medicine and Biotech Research and Innovation Center (BRIC)University of CopenhagenCopenhagenDenmark
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40
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PD-L1 tumor expression is associated with poor prognosis and systemic immunosuppression in glioblastoma. J Neurooncol 2022; 156:453-464. [DOI: 10.1007/s11060-021-03907-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2021] [Accepted: 11/22/2021] [Indexed: 10/19/2022]
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Chaddad A, Daniel P, Zhang M, Rathore S, Sargos P, Desrosiers C, Niazi T. Deep radiomic signature with immune cell markers predicts the survival of glioma patients. Neurocomputing 2022. [DOI: 10.1016/j.neucom.2020.10.117] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/09/2023]
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Liu Z, Ji H, Fu W, Ma S, Zhao H, Wang F, Dong J, Yan X, Zhang J, Wang N, Wu J, Hu S. IGFBPs were associated with stemness, inflammation, extracellular matrix remodeling and poor prognosis of low-grade glioma. Front Endocrinol (Lausanne) 2022; 13:943300. [PMID: 35992105 PMCID: PMC9381844 DOI: 10.3389/fendo.2022.943300] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/13/2022] [Accepted: 07/01/2022] [Indexed: 12/13/2022] Open
Abstract
BACKGROUND The IGFBP family of insulin-like growth factor binding proteins has important biological functions in the organism. However, the role of the IGFBP family in low-grade glioma (LGG) has not been fully explored. METHODS We validated the clinical value of the IGFBP family using RNA-seq and clinical data of LGG in the TCGA and constructed an IGFBPScore using LASSO-regression analysis for prognosis prediction, subtype determination, and treatment sensitivity determination. Subsequently, we explored the role of the IGFBP family in the development of LGG using PanCanAtlas data. RESULTS Our results suggest that most IGFBP family members were aberrantly expressed and were strongly associated with poor prognosis in LGG. By constructing an IGFBPScore representing the IGFBP family, we found that tumor samples with a high IGFBPScore had a glioblastoma-like mutation pattern characterized by IDH1wt, EGFRmut, PTENmut, and NF1mut with hypo-methylation and glioma stem cell (GSC) diversity. In contrast, the low IGFBPScore group was characterized by IDH1mut accompanied by TP53mut, CICmut, and ATRXmut, and had hyper-methylation status as well as the GSC restriction. Additionally, the high-IGFBPScore group had a high inflammation phenotype with increased immune antigenicity and increased infiltration of immune molecules and cells, as well as a high extracellular matrix phenotype and enhanced multiple metabolic pathways compared with the immune-quiet phenotype of the low-IGFBPScore group, which was strongly associated with poor prognosis. CONCLUSION Our study provides a summary analysis and a theoretical basis for the biological role and clinical value of the IGFBP family in LGG, providing an important therapeutic target for LGG.
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Affiliation(s)
- Zhihui Liu
- Department of Neurosurgery, Cancer Center, Zhejiang Provincial People’s Hospital Affiliated to Hangzhou Medical College, Hangzhou, China
- Department of Neurosurgery, The Second Affiliated Hospital of Harbin Medical University, Harbin, China
- The Key Laboratory of Myocardial Ischemia, Ministry of Education, Harbin, China
| | - Hang Ji
- Department of Neurosurgery, West China Hospital, Sichuan University, Sichuan, China
- *Correspondence: Hang Ji, ; Jiasheng Wu, ; Shaoshan Hu,
| | - Wenchao Fu
- Department of Neurosurgery, The Second Affiliated Hospital of Harbin Medical University, Harbin, China
- The Key Laboratory of Myocardial Ischemia, Ministry of Education, Harbin, China
| | - Shuai Ma
- Department of Neurosurgery, The Second Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Hongtao Zhao
- Department of Neurosurgery, Cancer Center, Zhejiang Provincial People’s Hospital Affiliated to Hangzhou Medical College, Hangzhou, China
- Department of Neurosurgery, The Second Affiliated Hospital of Harbin Medical University, Harbin, China
- The Key Laboratory of Myocardial Ischemia, Ministry of Education, Harbin, China
| | - Fang Wang
- Department of Neurosurgery, Cancer Center, Zhejiang Provincial People’s Hospital Affiliated to Hangzhou Medical College, Hangzhou, China
- Department of Neurosurgery, The Second Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Jiawei Dong
- Department of Neurosurgery, Cancer Center, Zhejiang Provincial People’s Hospital Affiliated to Hangzhou Medical College, Hangzhou, China
- Department of Neurosurgery, The Second Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Xiuwei Yan
- Department of Neurosurgery, Cancer Center, Zhejiang Provincial People’s Hospital Affiliated to Hangzhou Medical College, Hangzhou, China
- Department of Neurosurgery, The Second Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Jiheng Zhang
- Department of Neurosurgery, Cancer Center, Zhejiang Provincial People’s Hospital Affiliated to Hangzhou Medical College, Hangzhou, China
- Department of Neurosurgery, The Second Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Nan Wang
- Department of Neurosurgery, Cancer Center, Zhejiang Provincial People’s Hospital Affiliated to Hangzhou Medical College, Hangzhou, China
- Department of Neurosurgery, The Second Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Jiasheng Wu
- Department of Neurosurgery, The Second Affiliated Hospital of Harbin Medical University, Harbin, China
- *Correspondence: Hang Ji, ; Jiasheng Wu, ; Shaoshan Hu,
| | - Shaoshan Hu
- Department of Neurosurgery, Cancer Center, Zhejiang Provincial People’s Hospital Affiliated to Hangzhou Medical College, Hangzhou, China
- Department of Neurosurgery, The Second Affiliated Hospital of Harbin Medical University, Harbin, China
- *Correspondence: Hang Ji, ; Jiasheng Wu, ; Shaoshan Hu,
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Mahmoud AB, Ajina R, Aref S, Darwish M, Alsayb M, Taher M, AlSharif SA, Hashem AM, Alkayyal AA. Advances in immunotherapy for glioblastoma multiforme. Front Immunol 2022; 13:944452. [PMID: 36311781 PMCID: PMC9597698 DOI: 10.3389/fimmu.2022.944452] [Citation(s) in RCA: 49] [Impact Index Per Article: 16.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2022] [Accepted: 09/23/2022] [Indexed: 02/05/2023] Open
Abstract
Glioblastoma multiforme (GBM) is the most common and aggressive malignant brain tumor of the central nervous system and has a very poor prognosis. The current standard of care for patients with GBM involves surgical resection, radiotherapy, and chemotherapy. Unfortunately, conventional therapies have not resulted in significant improvements in the survival outcomes of patients with GBM; therefore, the overall mortality rate remains high. Immunotherapy is a type of cancer treatment that helps the immune system to fight cancer and has shown success in different types of aggressive cancers. Recently, healthcare providers have been actively investigating various immunotherapeutic approaches to treat GBM. We reviewed the most promising immunotherapy candidates for glioblastoma that have achieved encouraging results in clinical trials, focusing on immune checkpoint inhibitors, oncolytic viruses, nonreplicating viral vectors, and chimeric antigen receptor (CAR) immunotherapies.
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Affiliation(s)
- Ahmad Bakur Mahmoud
- College of Applied Medical Sciences, Taibah University, Almadinah Almunwarah, Saudi Arabia
- Strategic Research and Innovation Laboratories, Taibah University, Almadinah Almunwarah, Saudi Arabia
- King Abdullah International Medical Research Centre, King Saud University for Health Sciences, Ministry of National Guard Health Affairs, Riyadh, Saudi Arabia
- *Correspondence: Ahmad Bakur Mahmoud, ; Almohanad A. Alkayyal,
| | - Reham Ajina
- King Abdullah International Medical Research Centre, King Saud University for Health Sciences, Ministry of National Guard Health Affairs, Riyadh, Saudi Arabia
| | - Sarah Aref
- King Abdullah International Medical Research Centre, King Saud University for Health Sciences, Ministry of National Guard Health Affairs, Riyadh, Saudi Arabia
| | - Manar Darwish
- Strategic Research and Innovation Laboratories, Taibah University, Almadinah Almunwarah, Saudi Arabia
| | - May Alsayb
- College of Applied Medical Sciences, Taibah University, Almadinah Almunwarah, Saudi Arabia
| | - Mustafa Taher
- College of Applied Medical Sciences, Taibah University, Almadinah Almunwarah, Saudi Arabia
- Strategic Research and Innovation Laboratories, Taibah University, Almadinah Almunwarah, Saudi Arabia
| | - Shaker A. AlSharif
- King Fahad Hospital, Ministry of Health, Almadinah Almunwarah, Saudi Arabia
| | - Anwar M. Hashem
- Vaccines and Immunotherapy Unit, King Fahd Medical Research Center; King Abdulaziz University, Jeddah, Saudi Arabia
- Department of Medical Microbiology and Parasitology, Faculty of Medicine, King Abdulaziz University, Jeddah, Saudi Arabia
| | - Almohanad A. Alkayyal
- Department of Medical Laboratory Technology, University of Tabuk, Tabuk, Saudi Arabia
- Immunology Research Program, King Abdullah International Medical Research Center, Riyadh, Saudi Arabia
- *Correspondence: Ahmad Bakur Mahmoud, ; Almohanad A. Alkayyal,
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Hwang EI, Sayour EJ, Flores CT, Grant G, Wechsler-Reya R, Hoang-Minh LB, Kieran MW, Salcido J, Prins RM, Figg JW, Platten M, Candelario KM, Hale PG, Blatt JE, Governale LS, Okada H, Mitchell DA, Pollack IF. The current landscape of immunotherapy for pediatric brain tumors. NATURE CANCER 2022; 3:11-24. [PMID: 35121998 DOI: 10.1038/s43018-021-00319-0] [Citation(s) in RCA: 33] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/08/2020] [Accepted: 11/24/2021] [Indexed: 02/06/2023]
Abstract
Pediatric central nervous system tumors are the most common solid malignancies in childhood, and aggressive therapy often leads to long-term sequelae in survivors, making these tumors challenging to treat. Immunotherapy has revolutionized prospects for many cancer types in adults, but the intrinsic complexity of treating pediatric patients and the scarcity of clinical studies of children to inform effective approaches have hampered the development of effective immunotherapies in pediatric settings. Here, we review recent advances and ongoing challenges in pediatric brain cancer immunotherapy, as well as considerations for efficient clinical translation of efficacious immunotherapies into pediatric settings.
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Affiliation(s)
- Eugene I Hwang
- Division of Oncology, Brain Tumor Institute, Children's National Hospital, Washington, DC, USA.
| | - Elias J Sayour
- Department of Neurosurgery, Preston A. Wells, Jr. Center for Brain Tumor Therapy, University of Florida, Gainesville, FL, USA
| | - Catherine T Flores
- Department of Neurosurgery, Preston A. Wells, Jr. Center for Brain Tumor Therapy, University of Florida, Gainesville, FL, USA
| | - Gerald Grant
- Division of Pediatric Neurosurgery, Lucile Packard Children's Hospital, Stanford University, Palo Alto, CA, USA
| | - Robert Wechsler-Reya
- Tumor Initiation & Maintenance Program, NCI-Designated Cancer Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, USA
| | - Lan B Hoang-Minh
- Department of Neurosurgery, Preston A. Wells, Jr. Center for Brain Tumor Therapy, University of Florida, Gainesville, FL, USA
| | | | | | - Robert M Prins
- Departments of Neurosurgery and Molecular and Medical Pharmacology, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA
| | - John W Figg
- Department of Neurosurgery, Preston A. Wells, Jr. Center for Brain Tumor Therapy, University of Florida, Gainesville, FL, USA
| | - Michael Platten
- Department of Neurology, Medical Faculty Mannheim, MCTN, Heidelberg University and CCU Brain Tumor Immunology, DKFZ, Heidelberg, Germany
| | - Kate M Candelario
- Department of Neurosurgery, Preston A. Wells, Jr. Center for Brain Tumor Therapy, University of Florida, Gainesville, FL, USA
| | - Paul G Hale
- Children's Brain Trust, Coral Springs, FL, USA
| | - Jason E Blatt
- Department of Neurosurgery, Preston A. Wells, Jr. Center for Brain Tumor Therapy, University of Florida, Gainesville, FL, USA
| | - Lance S Governale
- Department of Neurosurgery, Preston A. Wells, Jr. Center for Brain Tumor Therapy, University of Florida, Gainesville, FL, USA
| | - Hideho Okada
- Department of Neurosurgery, University of California, San Francisco, CA, USA
| | - Duane A Mitchell
- Department of Neurosurgery, Preston A. Wells, Jr. Center for Brain Tumor Therapy, University of Florida, Gainesville, FL, USA
| | - Ian F Pollack
- Department of Neurological Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
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Hernández A, Domènech M, Muñoz-Mármol AM, Carrato C, Balana C. Glioblastoma: Relationship between Metabolism and Immunosuppressive Microenvironment. Cells 2021; 10:cells10123529. [PMID: 34944036 PMCID: PMC8700075 DOI: 10.3390/cells10123529] [Citation(s) in RCA: 28] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2021] [Revised: 12/06/2021] [Accepted: 12/10/2021] [Indexed: 12/12/2022] Open
Abstract
Glioblastoma (GBM) is the most aggressive brain tumor in adults and is characterized by an immunosuppressive microenvironment. Different factors shaping this tumor microenvironment (TME) regulate tumor initiation, progression, and treatment response. Genetic alterations and metabolism pathways are two main elements that influence tumor immune cells and TME. In this manuscript, we review how both factors can contribute to an immunosuppressive state and overview the strategies being tested.
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Affiliation(s)
- Ainhoa Hernández
- B·ARGO (Badalona Applied Research Group of Oncology) Medical Oncology Department, Catalan Institute of Oncology Badalona, 08916 Badalona, Spain; (A.H.); (M.D.)
| | - Marta Domènech
- B·ARGO (Badalona Applied Research Group of Oncology) Medical Oncology Department, Catalan Institute of Oncology Badalona, 08916 Badalona, Spain; (A.H.); (M.D.)
| | - Ana M. Muñoz-Mármol
- Pathology Department, Hospital Universitari Germans Trias i Pujol, 08916 Badalona, Spain; (A.M.M.-M.); (C.C.)
| | - Cristina Carrato
- Pathology Department, Hospital Universitari Germans Trias i Pujol, 08916 Badalona, Spain; (A.M.M.-M.); (C.C.)
| | - Carmen Balana
- B·ARGO (Badalona Applied Research Group of Oncology) Medical Oncology Department, Catalan Institute of Oncology Badalona, 08916 Badalona, Spain; (A.H.); (M.D.)
- Correspondence: ; Tel.: +34-4978925
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Rudek LS, Zimmermann K, Galla M, Meyer J, Kuehle J, Stamopoulou A, Brand D, Sandalcioglu IE, Neyazi B, Moritz T, Rossig C, Altvater B, Falk CS, Abken H, Morgan MA, Schambach A. Generation of an NFκB-Driven Alpharetroviral "All-in-One" Vector Construct as a Potent Tool for CAR NK Cell Therapy. Front Immunol 2021; 12:751138. [PMID: 34804035 PMCID: PMC8595471 DOI: 10.3389/fimmu.2021.751138] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2021] [Accepted: 10/12/2021] [Indexed: 11/13/2022] Open
Abstract
Immune cell therapeutics are increasingly applied in oncology. Especially chimeric antigen receptor (CAR) T cells are successfully used to treat several B cell malignancies. Efforts to engineer CAR T cells for improved activity against solid tumors include co-delivery of pro-inflammatory cytokines in addition to CARs, via either constitutive cytokine expression or inducible cytokine expression triggered by CAR recognition of its target antigen-so-called "T cells redirected for universal cytokine-mediated killing" (TRUCKs) or fourth-generation CARs. Here, we tested the hypothesis that TRUCK principles could be expanded to improve anticancer functions of NK cells. A comparison of the functionality of inducible promoters responsive to NFAT or NFκB in NK cells showed that, in contrast to T cells, the inclusion of NFκB-responsive elements within the inducible promoter construct was essential for CAR-inducible expression of the transgene. We demonstrated that GD2CAR-specific activation induced a tight NFκB-promoter-driven cytokine release in NK-92 and primary NK cells together with an enhanced cytotoxic capacity against GD2+ target cells, also shown by increased secretion of cytolytic cytokines. The data demonstrate biologically relevant differences between T and NK cells that are important when clinically translating the TRUCK concept to NK cells for the treatment of solid malignancies.
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Affiliation(s)
- Loreen Sophie Rudek
- Institute of Experimental Hematology, Hannover Medical School, Hannover, Germany
| | - Katharina Zimmermann
- Institute of Experimental Hematology, Hannover Medical School, Hannover, Germany
| | - Melanie Galla
- Institute of Experimental Hematology, Hannover Medical School, Hannover, Germany
| | - Johann Meyer
- Institute of Experimental Hematology, Hannover Medical School, Hannover, Germany
| | - Johannes Kuehle
- Center for Molecular Medicine Cologne, University of Cologne, Cologne, Germany.,Department I of Internal Medicine, University Hospital Cologne, Cologne, Germany
| | - Andriana Stamopoulou
- Institute of Experimental Hematology, Hannover Medical School, Hannover, Germany
| | - Daniel Brand
- Institute of Experimental Hematology, Hannover Medical School, Hannover, Germany
| | - I Erol Sandalcioglu
- Department of Neurosurgery, Otto-von-Guericke University, Magdeburg, Germany
| | - Belal Neyazi
- Department of Neurosurgery, Otto-von-Guericke University, Magdeburg, Germany
| | - Thomas Moritz
- Institute of Experimental Hematology, Hannover Medical School, Hannover, Germany
| | - Claudia Rossig
- Department of Pediatric Hematology and Oncology, University Children's Hospital Muenster, Muenster, Germany
| | - Bianca Altvater
- Department of Pediatric Hematology and Oncology, University Children's Hospital Muenster, Muenster, Germany
| | - Christine S Falk
- Institute of Transplant Immunology, Integrated Research and Treatment Center Transplantation, Hannover Medical School, Hannover, Germany
| | - Hinrich Abken
- Regensburg Centre for Interventional Immunology, Department of Genetic Immunotherapy, University Hospital Regensburg, Regensburg, Germany
| | | | - Axel Schambach
- Institute of Experimental Hematology, Hannover Medical School, Hannover, Germany.,Division of Hematology/Oncology, Boston Children's Hospital, Harvard Medical School, Boston, MA, United States
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Ott M, Prins RM, Heimberger AB. The immune landscape of common CNS malignancies: implications for immunotherapy. Nat Rev Clin Oncol 2021; 18:729-744. [PMID: 34117475 PMCID: PMC11090136 DOI: 10.1038/s41571-021-00518-9] [Citation(s) in RCA: 64] [Impact Index Per Article: 16.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/28/2021] [Indexed: 02/06/2023]
Abstract
Immunotherapy has enabled remarkable therapeutic responses across cancers of various lineages, albeit with some notable exceptions such as glioblastoma. Several previous misconceptions, which have impaired progress in the past, including the presence and role of the blood-brain barrier and a lack of lymphatic drainage, have been refuted. Nonetheless, a subset of patients with brain metastases but, paradoxically, not the vast majority of those with gliomas are able to respond to immune-checkpoint inhibitors. Immune profiling of samples obtained from patients with central nervous system malignancies using techniques such as mass cytometry and single-cell sequencing along with experimental data from genetically engineered mouse models have revealed fundamental differences in immune composition and immunobiology that not only explain the differences in responsiveness to these agents but also lay the foundations for immunotherapeutic strategies that are applicable to gliomas. Herein, we review the emerging data on the differences in immune cell composition, function and interactions within central nervous system tumours and provide guidance on the development of novel immunotherapies for these historically difficult-to-treat cancers.
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Affiliation(s)
- Martina Ott
- Department of Neurosurgery, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Robert M Prins
- Departments of Neurosurgery and Molecular and Medical Pharmacology, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA
| | - Amy B Heimberger
- Department of Neurosurgery, Northwestern University, Chicago, IL, USA.
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Khan S, Mahalingam R, Sen S, Martinez-Ledesma E, Khan A, Gandy K, Lang FF, Sulman EP, Alfaro-Munoz KD, Majd NK, Balasubramaniyan V, de Groot JF. Intrinsic Interferon Signaling Regulates the Cell Death and Mesenchymal Phenotype of Glioblastoma Stem Cells. Cancers (Basel) 2021; 13:cancers13215284. [PMID: 34771447 PMCID: PMC8582372 DOI: 10.3390/cancers13215284] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2021] [Accepted: 10/15/2021] [Indexed: 01/12/2023] Open
Abstract
Simple Summary Interferon signaling is mostly studied in the context of immune cells. However, its role in glioma cancer cells is unclear. This study aimed to investigate the role of cancer-cell-intrinsic IFN signaling in tumorigenesis in glioblastoma (GBM). We found that GSCs and GBM tumors exhibited differential cell-intrinsic type I and type II IFN signaling, and the high IFN/STAT1 signaling was associated with mesenchymal phenotype and poor survival in glioma patients. IFN-β exposure induced cell death in GSCs with intrinsically high IFN/STAT1 signaling, and this effect was abolished by inhibition of IFN/STAT1 signaling. A subset of GBM patients with high IFN/STAT1 may benefit from the IFN-β therapy. Abstract Interferon (IFN) signaling contributes to stemness, cell proliferation, cell death, and cytokine signaling in cancer and immune cells; however, the role of IFN signaling in glioblastoma (GBM) and GBM stem-like cells (GSCs) is unclear. Here, we investigated the role of cancer-cell-intrinsic IFN signaling in tumorigenesis in GBM. We report here that GSCs and GBM tumors exhibited differential cell-intrinsic type I and type II IFN signaling, and high IFN/STAT1 signaling was associated with mesenchymal phenotype and poor survival outcomes. In addition, chronic inhibition of IFN/STAT1 signaling decreased cell proliferation and mesenchymal signatures in GSCs with intrinsically high IFN/STAT1 signaling. IFN-β exposure induced apoptosis in GSCs with intrinsically high IFN/STAT1 signaling, and this effect was abolished by the pharmacological inhibitor ruxolitinib and STAT1 knockdown. We provide evidence for targeting IFN signaling in a specific sub-group of GBM patients. IFN-β may be a promising candidate for adjuvant GBM therapy.
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Affiliation(s)
- Sabbir Khan
- Department of Neuro-Oncology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030, USA; (S.K.); (S.S.); (E.M.-L.); (K.G.); (K.D.A.-M.); (N.K.M.)
| | - Rajasekaran Mahalingam
- Department of Symptom Research, MD Anderson Cancer Center, The University of Texas, Houston, TX 770030, USA;
| | - Shayak Sen
- Department of Neuro-Oncology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030, USA; (S.K.); (S.S.); (E.M.-L.); (K.G.); (K.D.A.-M.); (N.K.M.)
| | - Emmanuel Martinez-Ledesma
- Department of Neuro-Oncology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030, USA; (S.K.); (S.S.); (E.M.-L.); (K.G.); (K.D.A.-M.); (N.K.M.)
- Tecnologico de Monterrey, Escuela de Medicina y Ciencias de la Salud, Ave. Morones Prieto 3000, Monterrey 64710, Mexico
| | - Arshad Khan
- Department of Pathology and Genomic Medicine, Houston Methodist Research Institute, Houston, TX 77030, USA;
| | - Kaitlin Gandy
- Department of Neuro-Oncology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030, USA; (S.K.); (S.S.); (E.M.-L.); (K.G.); (K.D.A.-M.); (N.K.M.)
| | - Frederick F. Lang
- Department of Neurosurgery, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030, USA;
| | - Erik P. Sulman
- Department of Radiation Oncology, New York University, New York, NY 10016, USA;
| | - Kristin D. Alfaro-Munoz
- Department of Neuro-Oncology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030, USA; (S.K.); (S.S.); (E.M.-L.); (K.G.); (K.D.A.-M.); (N.K.M.)
| | - Nazanin K. Majd
- Department of Neuro-Oncology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030, USA; (S.K.); (S.S.); (E.M.-L.); (K.G.); (K.D.A.-M.); (N.K.M.)
| | - Veerakumar Balasubramaniyan
- Department of Neuro-Oncology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030, USA; (S.K.); (S.S.); (E.M.-L.); (K.G.); (K.D.A.-M.); (N.K.M.)
- Correspondence: (V.B.); (J.F.d.G.)
| | - John F. de Groot
- Department of Neuro-Oncology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030, USA; (S.K.); (S.S.); (E.M.-L.); (K.G.); (K.D.A.-M.); (N.K.M.)
- Department of Neuro-Oncology, University of California, San Francisco, CA 94143, USA
- Correspondence: (V.B.); (J.F.d.G.)
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Chen R, Wang X, Dai Z, Wang Z, Wu W, Hu Z, Zhang X, Liu Z, Zhang H, Cheng Q. TNFSF13 Is a Novel Onco-Inflammatory Marker and Correlates With Immune Infiltration in Gliomas. Front Immunol 2021; 12:713757. [PMID: 34712225 PMCID: PMC8546343 DOI: 10.3389/fimmu.2021.713757] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2021] [Accepted: 09/13/2021] [Indexed: 12/21/2022] Open
Abstract
Existing therapeutic strategies for gliomas are restricted; hence, exploration for novel diagnostic indicator and treatment is essential. Here, we performed bioinformatic analyses for TNFSF13 (also known as APRIL), a proliferation-inducing ligand of the tumor necrosis factor (TNF) superfamily, aiming to assess its potential for predicting glioma patient's prognosis and targeted therapy. TNFSF13 expression was upregulated in the increase of tumor grades based on Xiangya cohort. In high TNFSF13 gliomas, somatic mutation was proved to correlate with amplification of EGFR and deletion of CDKN2A; while mutation of IDH1 was more frequently observed in low TNFSF13 group. We also confirmed the positive correlation between TNFSF13 and infiltrating immune and stromal cells in glioma microenvironment. Further, TNFSF13 was found to be involved in immunosuppression via diverse immunoregulation pathways and was associated with other immune checkpoints and inflammation. Single-cell sequencing revealed an abundant expression of TNFSF13 in neoplastic cells and M2 macrophages, which TNFSF13 might potentially regulate the cell communication via IL-8, C3, and CD44. Lastly, TNFSF13 mediated the activities of transcription factors including FOXO3, MEIS2, and IRF8. Our analyses demonstrated the relevance between TNFSF13 and glioma progress and indicated the potential of TNFSF13 as a novel diagnostic onco-inflammatory biomarker and immunotherapy target of gliomas.
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Affiliation(s)
- Rui Chen
- Department of Neurosurgery, The Affiliated Nanhua Hospital, Hengyang Medical School, University of South China, Hengyang, China
| | - Xinxing Wang
- Department of Orthopedics, The Third Xiangya Hospital, Central South University, Changsha, China
| | - Ziyu Dai
- Department of Neurosurgery, Xiangya Hospital, Central South University, Changsha, China
| | - Zeyu Wang
- Department of Neurosurgery, Xiangya Hospital, Central South University, Changsha, China
| | - Wantao Wu
- Department of Oncology, Xiangya Hospital, Central South University, Changsha, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China
| | - Zhengang Hu
- Department of Neurosurgery, Xiangya Hospital, Central South University, Changsha, China
| | - Xun Zhang
- Department of Neurosurgery, Xiangya Hospital, Central South University, Changsha, China
| | - Zhixiong Liu
- Department of Neurosurgery, Xiangya Hospital, Central South University, Changsha, China
| | - Hao Zhang
- Department of Neurosurgery, Xiangya Hospital, Central South University, Changsha, China
| | - Quan Cheng
- Department of Neurosurgery, Xiangya Hospital, Central South University, Changsha, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China
- Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha, China
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50
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Alghamri MS, McClellan BL, Avvari RP, Thalla R, Carney S, Hartlage CS, Haase S, Ventosa M, Taher A, Kamran N, Zhang L, Faisal SM, Núñez FJ, Garcia-Fabiani MB, Al-Holou WN, Orringer D, Hervey-Jumper S, Heth J, Patil PG, Eddy K, Merajver SD, Ulintz PJ, Welch J, Gao C, Liu J, Núñez G, Hambardzumyan D, Lowenstein PR, Castro MG. G-CSF secreted by mutant IDH1 glioma stem cells abolishes myeloid cell immunosuppression and enhances the efficacy of immunotherapy. SCIENCE ADVANCES 2021; 7:eabh3243. [PMID: 34586841 PMCID: PMC8480930 DOI: 10.1126/sciadv.abh3243] [Citation(s) in RCA: 62] [Impact Index Per Article: 15.5] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/01/2021] [Accepted: 08/06/2021] [Indexed: 05/24/2023]
Abstract
Mutant isocitrate-dehydrogenase 1 (mIDH1) synthesizes the oncometabolite 2-hydroxyglutarate (2HG), which elicits epigenetic reprogramming of the glioma cells’ transcriptome by inhibiting DNA and histone demethylases. We show that the efficacy of immune-stimulatory gene therapy (TK/Flt3L) is enhanced in mIDH1 gliomas, due to the reprogramming of the myeloid cells’ compartment infiltrating the tumor microenvironment (TME). We uncovered that the immature myeloid cells infiltrating the mIDH1 TME are mainly nonsuppressive neutrophils and preneutrophils. Myeloid cell reprogramming was triggered by granulocyte colony-stimulating factor (G-CSF) secreted by mIDH1 glioma stem/progenitor-like cells. Blocking G-CSF in mIDH1 glioma–bearing mice restores the inhibitory potential of the tumor-infiltrating myeloid cells, accelerating tumor progression. We demonstrate that G-CSF reprograms bone marrow granulopoiesis, resulting in noninhibitory myeloid cells within mIDH1 glioma TME and enhancing the efficacy of immune-stimulatory gene therapy.
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Affiliation(s)
- Mahmoud S. Alghamri
- Department of Neurosurgery, University of Michigan Medical School, Ann Arbor, MI 48109, USA
- Department of Cell and Developmental Biology, University of Michigan Medical School, Ann Arbor, MI 48109, USA
| | - Brandon L. McClellan
- Department of Neurosurgery, University of Michigan Medical School, Ann Arbor, MI 48109, USA
- Department of Cell and Developmental Biology, University of Michigan Medical School, Ann Arbor, MI 48109, USA
- Graduate Program in Immunology, University of Michigan Medical School, Ann Arbor, MI 48109, USA
| | - Ruthvik P. Avvari
- Department of Neurosurgery, University of Michigan Medical School, Ann Arbor, MI 48109, USA
- Department of Cell and Developmental Biology, University of Michigan Medical School, Ann Arbor, MI 48109, USA
| | - Rohit Thalla
- Department of Neurosurgery, University of Michigan Medical School, Ann Arbor, MI 48109, USA
- Department of Cell and Developmental Biology, University of Michigan Medical School, Ann Arbor, MI 48109, USA
| | - Stephen Carney
- Department of Neurosurgery, University of Michigan Medical School, Ann Arbor, MI 48109, USA
- Department of Cell and Developmental Biology, University of Michigan Medical School, Ann Arbor, MI 48109, USA
| | - Carson S. Hartlage
- Department of Neurosurgery, University of Michigan Medical School, Ann Arbor, MI 48109, USA
- Department of Cell and Developmental Biology, University of Michigan Medical School, Ann Arbor, MI 48109, USA
| | - Santiago Haase
- Department of Neurosurgery, University of Michigan Medical School, Ann Arbor, MI 48109, USA
- Department of Cell and Developmental Biology, University of Michigan Medical School, Ann Arbor, MI 48109, USA
| | - Maria Ventosa
- Department of Neurosurgery, University of Michigan Medical School, Ann Arbor, MI 48109, USA
- Department of Cell and Developmental Biology, University of Michigan Medical School, Ann Arbor, MI 48109, USA
| | - Ayman Taher
- Department of Neurosurgery, University of Michigan Medical School, Ann Arbor, MI 48109, USA
- Department of Cell and Developmental Biology, University of Michigan Medical School, Ann Arbor, MI 48109, USA
| | - Neha Kamran
- Department of Neurosurgery, University of Michigan Medical School, Ann Arbor, MI 48109, USA
- Department of Cell and Developmental Biology, University of Michigan Medical School, Ann Arbor, MI 48109, USA
| | - Li Zhang
- Department of Neurosurgery, University of Michigan Medical School, Ann Arbor, MI 48109, USA
- Department of Cell and Developmental Biology, University of Michigan Medical School, Ann Arbor, MI 48109, USA
| | - Syed Mohd Faisal
- Department of Neurosurgery, University of Michigan Medical School, Ann Arbor, MI 48109, USA
- Department of Cell and Developmental Biology, University of Michigan Medical School, Ann Arbor, MI 48109, USA
| | - Felipe J. Núñez
- Department of Neurosurgery, University of Michigan Medical School, Ann Arbor, MI 48109, USA
- Department of Cell and Developmental Biology, University of Michigan Medical School, Ann Arbor, MI 48109, USA
| | - María Belén Garcia-Fabiani
- Department of Neurosurgery, University of Michigan Medical School, Ann Arbor, MI 48109, USA
- Department of Cell and Developmental Biology, University of Michigan Medical School, Ann Arbor, MI 48109, USA
| | - Wajd N. Al-Holou
- Department of Neurosurgery, University of Michigan Medical School, Ann Arbor, MI 48109, USA
| | - Daniel Orringer
- Department of Neurosurgery, University of Michigan Medical School, Ann Arbor, MI 48109, USA
| | - Shawn Hervey-Jumper
- Department of Neurosurgery, University of California San Francisco, San Francisco, CA 94143, USA
| | - Jason Heth
- Department of Neurosurgery, University of Michigan Medical School, Ann Arbor, MI 48109, USA
| | - Parag G. Patil
- Department of Neurosurgery, University of Michigan Medical School, Ann Arbor, MI 48109, USA
| | - Karen Eddy
- Department of Neurosurgery, University of Michigan Medical School, Ann Arbor, MI 48109, USA
| | - Sofia D. Merajver
- Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI 48109, USA
| | - Peter J. Ulintz
- Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI 48109, USA
| | - Joshua Welch
- Department of Computational Medicine and Bioinformatics, University of Michigan Medical School, Ann Arbor, MI 48109, USA
| | - Chao Gao
- Department of Computational Medicine and Bioinformatics, University of Michigan Medical School, Ann Arbor, MI 48109, USA
| | - Jialin Liu
- Department of Computational Medicine and Bioinformatics, University of Michigan Medical School, Ann Arbor, MI 48109, USA
| | - Gabriel Núñez
- Department of Pathology, University of Michigan Medical School, Ann Arbor, MI 48109, USA
| | - Dolores Hambardzumyan
- Department of Oncological Sciences, The Tisch Cancer Institute, and Department of Neurosurgery, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
| | - Pedro R. Lowenstein
- Department of Neurosurgery, University of Michigan Medical School, Ann Arbor, MI 48109, USA
- Department of Cell and Developmental Biology, University of Michigan Medical School, Ann Arbor, MI 48109, USA
- Rogel Cancer Center, University of Michigan, Ann Arbor, MI 48109, USA
| | - Maria G. Castro
- Department of Neurosurgery, University of Michigan Medical School, Ann Arbor, MI 48109, USA
- Department of Cell and Developmental Biology, University of Michigan Medical School, Ann Arbor, MI 48109, USA
- Rogel Cancer Center, University of Michigan, Ann Arbor, MI 48109, USA
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