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Vetsika EK, Katsianou MA, Sarantis P, Palamaris K, Papavassiliou AG, Piperi C. Pediatric gliomas immunity challenges and immunotherapy advances. Cancer Lett 2025; 618:217640. [PMID: 40090572 DOI: 10.1016/j.canlet.2025.217640] [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: 02/11/2025] [Revised: 03/11/2025] [Accepted: 03/12/2025] [Indexed: 03/18/2025]
Abstract
Pediatric gliomas, the most frequent brain tumors in children, are characterized by heterogeneity and a unique tumor immune microenvironment. They are categorized into different subtypes, including low-grade gliomas like pilocytic astrocytomas and high-grade gliomas such as diffuse midline gliomas and diffuse intrinsic pontine gliomas, each exhibiting distinct immunological profiles. The tumor immune microenvironment in pediatric gliomas is shaped by cellular and non-cellular components, including immune cells, cytokines, and the extracellular matrix, involved in tumor progression, immune evasion, and response to therapy. While pediatric low-grade gliomas often display an immunosuppressed microenvironment, high-grade gliomas are characterized by complex immune infiltrates and intricate immunosuppressive mechanisms. The blood-brain barrier further obscures immune cell recruitment and therapeutic delivery. Despite advances in understanding adult gliomas, the immunobiology of pediatric tumors is poorly investigated, with limited data on the interactions between glioma cells and immune populations such as T and natural killer cells, as well as tumor-associated macrophages. Herein, we provide an update of the current knowledge on tumor immune microenvironment interactions in pediatric gliomas, highlighting the immunosuppressive mechanisms and emerging immunotherapeutic strategies aiming at overcoming these barriers to improve clinical outcomes for affected children.
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Affiliation(s)
- Eleni-Kyriaki Vetsika
- Centre of New Biotechnologies and Precision Medicine (CNBPM), School of Medicine, National and Kapodistrian University of Athens, Athens, Greece
| | - Maria A Katsianou
- Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, Athens, Greece
| | - Panagiotis Sarantis
- Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, Athens, Greece
| | - Kostas Palamaris
- First Department of Pathology, School of Medicine, National and Kapodistrian University of Athens, 10679, Athens, Greece
| | - Athanasios G Papavassiliou
- Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, Athens, Greece
| | - Christina Piperi
- Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, Athens, Greece.
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2
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Pang L, Guo S, Huang Y, Khan F, Liu Y, Zhou F, Lathia JD, Chen P. Targeting legumain-mediated cell-cell interaction sensitizes glioblastoma to immunotherapy in preclinical models. J Clin Invest 2025; 135:e186034. [PMID: 40131864 PMCID: PMC12077903 DOI: 10.1172/jci186034] [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] [Received: 08/15/2024] [Accepted: 03/17/2025] [Indexed: 03/27/2025] Open
Abstract
Tumor-associated macrophages (TAMs) are the most prominent immune cell population in the glioblastoma (GBM) tumor microenvironment and play critical roles in promoting tumor progression and immunosuppression. Here we identified that TAM-derived legumain (LGMN) exhibited a dual role in regulating the biology of TAMs and GBM cells. LGMN promoted macrophage infiltration in a cell-autonomous manner by activating the GSK3β/STAT3 pathway. Moreover, TAM-derived LGMN activated integrin αv/AKT/p65 signaling to drive GBM cell proliferation and survival. Targeting of LGMN-directed macrophage (inhibiting GSK3β and STAT3) and GBM cell (inhibiting integrin αv) mechanisms resulted in an antitumor effect in immunocompetent GBM mouse models that was further enhanced by combination with anti-PD-1 therapy. Our study reveals a paracrine and autocrine mechanism of TAM-derived LGMN that promotes GBM progression and immunosuppression, providing effective therapeutic targets to improve immunotherapy in GBM.
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Affiliation(s)
- Lizhi Pang
- Department of Cancer Biology, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, USA
- Department of Neurological Surgery, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA
| | - Songlin Guo
- Department of Neurological Surgery, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA
| | - Yuyun Huang
- Department of Cancer Biology, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, USA
| | - Fatima Khan
- Department of Cancer Biology, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, USA
| | - Yang Liu
- Department of Cancer Biology, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, USA
| | - Fei Zhou
- Department of Cancer Biology, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, USA
- Department of Neurological Surgery, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA
| | - Justin D. Lathia
- Department of Cardiovascular and Metabolic Sciences, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, USA
- Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, Ohio, USA
- Rose Ella Burkhardt Brain Tumor & Neuro-Oncology Center, Cleveland Clinic, Cleveland, Ohio, USA
- Case Comprehensive Cancer Center, Cleveland, Ohio, USA
| | - Peiwen Chen
- Department of Cancer Biology, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, USA
- Department of Neurological Surgery, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA
- Case Comprehensive Cancer Center, Cleveland, Ohio, USA
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Wilson AM, Jacobs MM, Lambert TY, Valada A, Meloni G, Gilmore E, Murray J, Morgello S, Akbarian S. Transcriptional impacts of substance use disorder and HIV on human ventral midbrain neurons and microglia. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2025:2025.02.05.636667. [PMID: 39974894 PMCID: PMC11838593 DOI: 10.1101/2025.02.05.636667] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/21/2025]
Abstract
For people with HIV (PWH), substance use disorders (SUDs) are a prominent neurological risk factor, and the impacts of both on dopaminergic pathways are a potential point of deleterious convergence. Here, we profile, at single nucleus resolution, the substantia nigra (SN) transcriptomes of 90 postmortem donors in the context of chronic HIV and opioid/cocaine SUD, including 67 prospectively characterized PWH. We report altered microglial expression for hundreds of pro- and anti-inflammatory regulators attributable to HIV, and separately, to SUD. Stepwise, progressive microglial dysregulation, coupled to altered SN dopaminergic and GABAergic signaling, was associated with SUD/HIV dual diagnosis and further with lack of viral suppression in blood. In virologically suppressed donors, SUD comorbidity was associated with microglial transcriptional changes permissive for HIV infection. We report HIV-related downregulation of monoamine reuptake transporters specifically in dopaminergic neurons regardless of SUD status or viral load, and additional transcriptional signatures consistent with selective vulnerability of SN dopamine neurons.
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Affiliation(s)
- Alyssa M. Wilson
- Department of Neurology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
- Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
| | - Michelle M. Jacobs
- Department of Neurology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
| | - Tova Y. Lambert
- Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
| | - Aditi Valada
- Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
| | - Gregory Meloni
- Department of Neurology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
| | - Evan Gilmore
- Department of Neurology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
| | - Jacinta Murray
- Department of Neurology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
| | - Susan Morgello
- Department of Neurology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
- Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
- Department of Pathology, Molecular and Cell Based Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
| | - Schahram Akbarian
- Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
- Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
- Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
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Sun S, Chen X, Ding N, Zhang M, Li X, Chen L, Sun K, Liu Y. Gamma-aminobutyric acid-mediated neuro-immune interactions in glioblastoma: Implications for prognosis and immunotherapy response. Life Sci 2024; 357:123067. [PMID: 39322177 DOI: 10.1016/j.lfs.2024.123067] [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: 03/12/2024] [Revised: 09/11/2024] [Accepted: 09/16/2024] [Indexed: 09/27/2024]
Abstract
AIMS This study aimed to investigate the role of gamma-aminobutyric acid (GABA) in the glioblastoma (GBM) tumor immune microenvironment (TIME) and its impact on prognosis and response to immunotherapy. MAIN METHODS This study employed single-cell RNA sequencing (scRNA-seq) to delineate the TIME of GBM, utilized non-negative matrix factorization (NMF) for GABA-associated cell clustering, and performed pseudotime analysis for cellular trajectories. Additionally, we integrated immunohistochemistry (IHC), immunofluorescence (IF), and protein-protein interaction (PPI) analysis to explore the regulatory mechanisms within the tumor microenvironment. KEY FINDINGS The study identified distinct GABA-associated immune cell subtypes, particularly macrophages and T-cells, with unique gene expression and developmental trajectories. The development of the GABA-associated scoring model (GABAAS), introduced novel prognostic indicators, enhancing our ability to predict patient outcomes. This study also suggests that GABA-related genes, including NDRG2 and TIMP1, play a crucial role in immune modulation, with potential implications for immunotherapy responsiveness. SIGNIFICANCE The findings underscore the potential of targeting GABA-related genes (NDRG2 and TIMP1) and M2 macrophage to reshape the glioblastoma immune landscape, offering a new frontier in personalized neuro-immunotherapy. This approach holds promise to counter individual tumor immunosuppressive mechanisms, enhancing patient outcomes.
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Affiliation(s)
- Shanyue Sun
- Department of Neurosurgery, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, China.
| | - Xinyuan Chen
- 4+4 Medical Doctor Program, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
| | - Nannan Ding
- Department of Nephrology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, China
| | - Miao Zhang
- Department of Radiology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, China
| | - Xiaoru Li
- Department of Neurosurgery, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, China
| | - Lin Chen
- Department of Neurosurgery, The Affiliated Hospital of Southwest Medical University, Luzhou, China
| | - Kai Sun
- Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, China; College of Medical Information and Artificial Intelligence & Central Hospital Affiliated to Shandong First Medical University, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, Shandong, China.
| | - Yingchao Liu
- Department of Neurosurgery, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, China.
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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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Richard SA, Roy SK, Asiamah EA. Pivotal Role of Cranial Irradiation-Induced Peripheral, Intrinsic, and Brain-Engrafting Macrophages in Malignant Glioma. Clin Med Insights Oncol 2024; 18:11795549241282098. [PMID: 39421649 PMCID: PMC11483687 DOI: 10.1177/11795549241282098] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2024] [Accepted: 08/20/2024] [Indexed: 10/19/2024] Open
Abstract
Malignant (high-grade) gliomas are aggressive intrinsic brain tumors that diffusely infiltrate the brain parenchyma. They comprise of World Health Organization (WHO) grade III and IV gliomas. Ionizing radiation or irradiation (IR) is frequently utilized in the treatment of both primary as well as metastatic brain tumors. On the contrary, macrophages (MΦ) are the most copious infiltrating immune cells of all the different cell types colonizing glioma. MΦ at tumor milieu are referred to as tumor-associated macrophages (TAMΦ). In malignant gliomas milieu, TAMΦ are also polarized into two distinct phenotypes such as M1 TAMΦ or M2 TAMΦ, which are capable of inhibiting or promoting tumor growth, respectively. Cranial-IR such as x- and γ-IR are sufficient to induce the migration of peripherally derived MΦ into the brain parenchyma. The IR facilitate a more immunosuppressive milieu via the stimulation of efferocytosis in TAMΦ, and an upsurge of tumor cell engulfment by TAMΦ exhibited detrimental effect of the anti-tumoral immune response in glioma. The MΦ inside the tumor mass are associated with multiple phenomena that include IR resistance and enrichment of the M2 MΦ after IR is able to facilitate glioblastoma multiforme (GBM) recurrence. Reviews on the role of cranial IR-induced peripheral and brain-engrafting macrophages (BeMΦ) in glioma are lacking. Specifically, most studies on peripheral, intrinsic as well as beMΦ on IR focus on WHO grade III and IV. Thus, this review precisely focuses primary on WHO grade III as well as IV gliomas.
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Affiliation(s)
- Seidu A Richard
- Department of Biochemistry and Forensic Sciences, School of Chemical and Biochemical Sciences, C. K. Tedam University of Technology and Applied Sciences (CKT-UTAS), UK, Ghana
- Institute of Neuroscience, Third Affiliated Hospital, Zhengzhou University, Zhengzhou, China
| | - Sagor Kumar Roy
- Department of Neurology, TMSS Medical College and Hospital, Bogura, Bangladesh
| | - Emmanuel Akomanin Asiamah
- Department of Medical Laboratory Sciences, School of Allied Health Sciences, University of Health and Allied Sciences, Ho, Ghana
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Li L, Zhang T, Xiao M, Lu Y, Gao L. Brain macrophage senescence in glioma. Semin Cancer Biol 2024; 104-105:46-60. [PMID: 39098625 DOI: 10.1016/j.semcancer.2024.07.005] [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: 06/07/2024] [Revised: 07/20/2024] [Accepted: 07/29/2024] [Indexed: 08/06/2024]
Abstract
Gliomas are a diverse group of primary central nervous system neoplasms with no curative therapies available. Brain macrophages comprise microglia in the brain parenchyma, border-associated macrophages in the meningeal-choroid plexus-perivascular space and monocyte-derived macrophages infiltrating the brain. With the great improvement of our recognition of brain macrophages, diverse macrophage populations have been found in the context of glioma, which exhibit functional and phenotypic heterogeneity. We have long thought that brain macrophage senescence is detrimental, manifested by specialized forms of persistent cell cycle arrest and chronic low-grade inflammation. Persistent senescence of macrophages may result in immune dysfunction, potentially contributing to glioma initiation and development. Given the crucial roles played by brain macrophages in glioma, we unravel how brain macrophages undergo reprogramming and their contribution to glioma. We outline general molecular alterations and specific biomarkers in senescent brain macrophages, as well as functional changes (such as metabolism, autophagy, phagocytosis, antigen presentation, and infiltration and recruitment). In addition, recent advances in genetic regulation and mechanisms linked to senescent brain macrophages are discussed. In particular, this review emphasizes the contribution of senescent brain macrophages to glioma, which may drive translational efforts to utilize brain macrophages as a prognostic marker or/and treatment target in glioma. An in-depth comprehending of how brain macrophage senescence functionally influences the tumor microenvironment will be key to our development of innovative therapeutics for glioma.
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Affiliation(s)
- Lu Li
- Department of Anesthesiology, Shengjing Hospital of China Medical University, Shenyang, Liaoning 110004, China
| | - Tianhe Zhang
- Department of Neurosurgery, The People's Hospital of China Medical University, The People's Hospital of Liaoning Province, Shenyang, Liaoning 110016, China
| | - Meiling Xiao
- Department of Rehabilitation, The Central Hospital of Shenyang Medical College, Shenyang, Liaoning 110024, China
| | - Yu Lu
- Rehabilitation Medicine Department, The People's Hospital of China Medical University, The People's Hospital of Liaoning Province, Shenyang, Liaoning 110016, China.
| | - Lin Gao
- Department of Rehabilitation, Shengjing Hospital of China Medical University, Shenyang, Liaoning 110004, China.
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Das AK, Sinha M, Singh SK, Chaudhary A, Boro AK, Agrawal M, Bhardwaj S, Kishore S, Kumari K. CAR T-cell therapy: a potential treatment strategy for pediatric midline gliomas. Acta Neurol Belg 2024; 124:1251-1261. [PMID: 38669002 DOI: 10.1007/s13760-024-02519-8] [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: 06/30/2023] [Accepted: 02/24/2024] [Indexed: 07/25/2024]
Abstract
Pediatric brain tumors are the primary cause of death in children with cancer. Diffuse midline glioma (DMG) and diffuse intrinsic pontine glioma (DIPG) are frequently unresectable due to their difficult access location, and 5-year survival remains less than 20%. Despite significant advances in tumor biology and genetics, treatment options remain limited and ineffective. Immunotherapy using T cells with a chimeric antigen receptor (CAR) that has been genetically engineered is quickly emerging as a new treatment option for these patients. High levels of expression were detected for both disialoganglioside (GD2) and B7-H3 in pediatric DMG/DIPG. Numerous studies have been conducted in recent years employing various generations of GD2-CAR T cells. The two most prevalent adverse effects found with this therapy are cytokine release syndrome, which varies in severity from mild constitutional symptoms to a high-grade disease associated with potentially fatal multi-organ failure, and neurotoxicity, known as CAR T-cell-related encephalopathy syndrome. During the acute phase of anticancer action, peri-tumoral neuro-inflammation might cause deadly hydrocephalus. The initial results of clinical trials show that the outcomes are not highly encouraging as B cell malignancies and myelomas. In vivo research on CAR T-cell therapy for DIPG has yielded encouraging results, but in human trials, the early results have shown potentially fatal side effects and very modest, but fleeting improvements. Solid tumors present a hindrance to CAR T-cell therapy because of the antigenic dilemma and the strong immune-suppressing tumor microenvironment.
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Affiliation(s)
- Anand Kumar Das
- All India Institute of Medical Sciences, Phulwari Sharif, Patna, Bihar, 801507, India
| | - Mainak Sinha
- All India Institute of Medical Sciences, Phulwari Sharif, Patna, Bihar, 801507, India
| | - Saraj Kumar Singh
- All India Institute of Medical Sciences, Phulwari Sharif, Patna, Bihar, 801507, India.
| | | | | | - Manish Agrawal
- SMS Medical College and Hospital, Jaipur, Rajasthan, India
| | - Sona Bhardwaj
- ESIC Medical College and Hospital, Patna, Bihar, India
| | - Simmi Kishore
- Indira Gandhi Institute of Medical Sciences, Patna, Bihar, India
| | - Katyayani Kumari
- Tata Memorial Centre and Homi Bhabha National Institute, Mumbai, Maharashtra, India
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Davis D, Wizel A, Drier Y. Accurate estimation of pathway activity in single cells for clustering and differential analysis. Genome Res 2024; 34:925-936. [PMID: 38981682 PMCID: PMC11293543 DOI: 10.1101/gr.278431.123] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2023] [Accepted: 06/05/2024] [Indexed: 07/11/2024]
Abstract
Inferring which and how biological pathways and gene sets change is a key question in many studies that utilize single-cell RNA sequencing. Typically, these questions are addressed by quantifying the enrichment of known gene sets in lists of genes derived from global analysis. Here we offer SiPSiC, a new method to infer pathway activity in every single cell. This allows more sensitive differential analysis and utilization of pathway scores to cluster cells and compute UMAP or other similar projections. We apply our method to COVID-19, lung adenocarcinoma and glioma data sets, and demonstrate its utility. SiPSiC analysis results are consistent with findings reported in previous studies in many cases, but SiPSiC also reveals the differential activity of novel pathways, enabling us to suggest new mechanisms underlying the pathophysiology of these diseases and demonstrating SiPSiC's high accuracy and sensitivity in detecting biological function and traits. In addition, we demonstrate how it can be used to better classify cells based on activity of biological pathways instead of single genes and its ability to overcome patient-specific artifacts.
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Affiliation(s)
- Daniel Davis
- The Lautenberg Center for Immunology and Cancer Research, IMRIC, Faculty of Medicine, Hebrew University of Jerusalem, Jerusalem 9112102, Israel
| | - Avishai Wizel
- The Lautenberg Center for Immunology and Cancer Research, IMRIC, Faculty of Medicine, Hebrew University of Jerusalem, Jerusalem 9112102, Israel
| | - Yotam Drier
- The Lautenberg Center for Immunology and Cancer Research, IMRIC, Faculty of Medicine, Hebrew University of Jerusalem, Jerusalem 9112102, Israel
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10
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Wu L, Zhao Z, Shin YJ, Yin Y, Raju A, Vaiyapuri TS, Idzham K, Son M, Lee Y, Sa JK, Chua JYH, Unal B, Zhai Y, Fan W, Huang L, Hu H, Gunaratne J, Nam DH, Jiang T, Tergaonkar V. Tumour microenvironment programming by an RNA-RNA-binding protein complex creates a druggable vulnerability in IDH-wild-type glioblastoma. Nat Cell Biol 2024; 26:1003-1018. [PMID: 38858501 PMCID: PMC11178504 DOI: 10.1038/s41556-024-01428-5] [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: 03/21/2023] [Accepted: 04/25/2024] [Indexed: 06/12/2024]
Abstract
Patients with IDH-wild-type glioblastomas have a poor five-year survival rate along with limited treatment efficacy due to immune cell (glioma-associated microglia and macrophages) infiltration promoting tumour growth and resistance. To enhance therapeutic options, our study investigated the unique RNA-RNA-binding protein complex LOC-DHX15. This complex plays a crucial role in driving immune cell infiltration and tumour growth by establishing a feedback loop between cancer and immune cells, intensifying cancer aggressiveness. Targeting this complex with blood-brain barrier-permeable small molecules improved treatment efficacy, disrupting cell communication and impeding cancer cell survival and stem-like properties. Focusing on RNA-RNA-binding protein interactions emerges as a promising approach not only for glioblastomas without the IDH mutation but also for potential applications beyond cancer, offering new avenues for developing therapies that address intricate cellular relationships in the body.
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Affiliation(s)
- Lele Wu
- Laboratory of NFκB Signalling, Institute of Molecular and Cell Biology (IMCB), Agency for Science Technology and Research (A*STAR), Singapore, Republic of Singapore
| | - Zheng Zhao
- Beijing Neurosurgical Institute, Capital Medical University, Beijing, China
| | - Yong Jae Shin
- Research Institute for Future Medicine, Samsung Medical Center, Seoul, Republic of Korea
| | - Yiyun Yin
- Beijing Neurosurgical Institute, Capital Medical University, Beijing, China
| | - Anandhkumar Raju
- Laboratory of NFκB Signalling, Institute of Molecular and Cell Biology (IMCB), Agency for Science Technology and Research (A*STAR), Singapore, Republic of Singapore
| | - Thamil Selvan Vaiyapuri
- Laboratory of NFκB Signalling, Institute of Molecular and Cell Biology (IMCB), Agency for Science Technology and Research (A*STAR), Singapore, Republic of Singapore
| | - Khaireen Idzham
- Laboratory of NFκB Signalling, Institute of Molecular and Cell Biology (IMCB), Agency for Science Technology and Research (A*STAR), Singapore, Republic of Singapore
| | - Miseol Son
- Research Institute for Future Medicine, Samsung Medical Center, Seoul, Republic of Korea
| | - Yeri Lee
- Research Institute for Future Medicine, Samsung Medical Center, Seoul, Republic of Korea
| | - Jason K Sa
- Department of Biomedical Sciences, Korea University College of Medicine, Seoul, Republic of Korea
| | - Joelle Yi Heng Chua
- Laboratory of NFκB Signalling, Institute of Molecular and Cell Biology (IMCB), Agency for Science Technology and Research (A*STAR), Singapore, Republic of Singapore
| | - Bilal Unal
- Laboratory of NFκB Signalling, Institute of Molecular and Cell Biology (IMCB), Agency for Science Technology and Research (A*STAR), Singapore, Republic of Singapore
| | - You Zhai
- Beijing Neurosurgical Institute, Capital Medical University, Beijing, China
| | - Wenhua Fan
- Beijing Neurosurgical Institute, Capital Medical University, Beijing, China
- Beijing Tiantan Hospital, Capital Medical University, Beijing, China
| | - Lijie Huang
- Beijing Neurosurgical Institute, Capital Medical University, Beijing, China
| | - Huimin Hu
- Beijing Neurosurgical Institute, Capital Medical University, Beijing, China
| | - Jayantha Gunaratne
- Laboratory of Translational Biomedical Proteomics, Institute of Molecular and Cell Biology (IMCB), Agency for Science Technology and Research (A*STAR), Singapore, Republic of Singapore
| | - Do-Hyun Nam
- Research Institute for Future Medicine, Samsung Medical Center, Seoul, Republic of Korea
- Department of Neurosurgery, Samsung Medical Center, Seoul, Republic of Korea
| | - Tao Jiang
- Beijing Neurosurgical Institute, Capital Medical University, Beijing, China.
- Beijing Tiantan Hospital, Capital Medical University, Beijing, China.
| | - Vinay Tergaonkar
- Laboratory of NFκB Signalling, Institute of Molecular and Cell Biology (IMCB), Agency for Science Technology and Research (A*STAR), Singapore, Republic of Singapore.
- Department of Pathology, Yong Loo Lin School of Medicine, National University of Singapore (NUS), Singapore, Republic of Singapore.
- Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore (NUS), Singapore, Republic of Singapore.
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11
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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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12
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Grishin A, Achkasova K, Kukhnina L, Sharova V, Ostapyuk M, Yashin K. Peritumoral Brain Zone in Astrocytoma: Morphology, Molecular Aspects, and Clinical Manifestations (Review). Sovrem Tekhnologii Med 2024; 16:79-88. [PMID: 39539752 PMCID: PMC11556047 DOI: 10.17691/stm2024.16.2.08] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2023] [Indexed: 11/16/2024] Open
Abstract
A peritumoral brain zone is an area between a tumor and nontumorous brain tissue with tumor cell infiltration. The identification of this area is sufficiently difficult due to the lack of clear morphological or some other criteria. Besides, its dimensions may vary considerably. In the present review, we have analyzed the available data on the morphological structure and metabolism of peritumoral zone in astrocytomes, and considered the main molecular and genetic aspects and clinical manifestations. Exploration of the peritumoral zone is of great importance for determining the extent of resection to prevent recurrence and to reveal the causes and mechanisms of continued tumor growth.
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Affiliation(s)
- A.S. Grishin
- Pathologist, Pathological Anatomy Unit, University Clinic; Privolzhsky Research Medical University, 10/1 Minin and Pozharsky Square, Nizhny Novgorod, 603005, Russia; Assistant, Department of Pathological Anatomy; Privolzhsky Research Medical University, 10/1 Minin and Pozharsky Square, Nizhny Novgorod, 603005, Russia
| | - K.A. Achkasova
- Junior Researcher, Laboratory of Optical Coherence Tomography, Institute of Experimental Oncology and Biomedical Technologies; Privolzhsky Research Medical University, 10/1 Minin and Pozharsky Square, Nizhny Novgorod, 603005, Russia
| | - L.S. Kukhnina
- Student; Privolzhsky Research Medical University, 10/1 Minin and Pozharsky Square, Nizhny Novgorod, 603005, Russia
| | - V.A. Sharova
- Student; Privolzhsky Research Medical University, 10/1 Minin and Pozharsky Square, Nizhny Novgorod, 603005, Russia
| | - M.V. Ostapyuk
- Neurosurgeon, Neurosurgery Unit, University Clinic; Privolzhsky Research Medical University, 10/1 Minin and Pozharsky Square, Nizhny Novgorod, 603005, Russia; Assistant, M.V. Kolokoltsev Department of Traumatology, Orthopedics, and Neurosurgery; Privolzhsky Research Medical University, 10/1 Minin and Pozharsky Square, Nizhny Novgorod, 603005, Russia
| | - K.S. Yashin
- MD, PhD, Neurosurgeon, Neurosurgery Unit, University Clinic; Privolzhsky Research Medical University, 10/1 Minin and Pozharsky Square, Nizhny Novgorod, 603005, Russia; Assistant, M.V. Kolokoltsev Department of Traumatology, Orthopedics, and Neurosurgery; Privolzhsky Research Medical University, 10/1 Minin and Pozharsky Square, Nizhny Novgorod, 603005, Russia; Oncologist, Outpatient Department; Nizhny Novgorod Regional Oncologic Dispensary, 11/1 Delovaya St., Nizhny Novgorod, 603163, Russia
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13
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Frederico SC, Sharma N, Darling C, Taori S, Dubinsky AC, Zhang X, Raphael I, Kohanbash G. Myeloid cells as potential targets for immunotherapy in pediatric gliomas. Front Pediatr 2024; 12:1346493. [PMID: 38523840 PMCID: PMC10960498 DOI: 10.3389/fped.2024.1346493] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/29/2023] [Accepted: 02/26/2024] [Indexed: 03/26/2024] Open
Abstract
Pediatric high-grade glioma (pHGG) including pediatric glioblastoma (pGBM) are highly aggressive pediatric central nervous system (CNS) malignancies. pGBM comprises approximately 3% of all pediatric CNS malignancies and has a 5-year survival rate of approximately 20%. Surgical resection and chemoradiation are often the standard of care for pGBM and pHGG, however, even with these interventions, survival for children diagnosed with pGBM and pHGG remains poor. Due to shortcomings associated with the standard of care, many efforts have been made to create novel immunotherapeutic approaches targeted to these malignancies. These efforts include the use of vaccines, cell-based therapies, and immune-checkpoint inhibitors. However, it is believed that in many pediatric glioma patients an immunosuppressive tumor microenvironment (TME) possess barriers that limit the efficacy of immune-based therapies. One of these barriers includes the presence of immunosuppressive myeloid cells. In this review we will discuss the various types of myeloid cells present in the glioma TME, including macrophages and microglia, myeloid-derived suppressor cells, and dendritic cells, as well as the specific mechanisms these cells can employ to enable immunosuppression. Finally, we will highlight therapeutic strategies targeted to these cells that are aimed at impeding myeloid-cell derived immunosuppression.
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Affiliation(s)
- Stephen C. Frederico
- University of Pittsburgh School of Medicine, Pittsburgh, PA, United States
- Harvard Medical School, Boston, MA, United States
- Dana-Farber Cancer Institute, Boston, MA, United States
- Department of Neurological Surgery, University of Pittsburgh, Pittsburgh, PA, United States
| | - Nikhil Sharma
- University of Pittsburgh School of Medicine, Pittsburgh, PA, United States
| | - Corbin Darling
- University of Pittsburgh School of Medicine, Pittsburgh, PA, United States
| | - Suchet Taori
- University of Pittsburgh School of Medicine, Pittsburgh, PA, United States
| | | | - Xiaoran Zhang
- Sloan Kettering Memorial Cancer Center, New York, NY, United States
| | - Itay Raphael
- Department of Neurological Surgery, University of Pittsburgh, Pittsburgh, PA, United States
| | - Gary Kohanbash
- Department of Neurological Surgery, University of Pittsburgh, Pittsburgh, PA, United States
- Department of Immunology, University of Pittsburgh, Pittsburgh, PA, United States
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14
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Khan F, Lin Y, Ali H, Pang L, Dunterman M, Hsu WH, Frenis K, Grant Rowe R, Wainwright DA, McCortney K, Billingham LK, Miska J, Horbinski C, Lesniak MS, Chen P. Lactate dehydrogenase A regulates tumor-macrophage symbiosis to promote glioblastoma progression. Nat Commun 2024; 15:1987. [PMID: 38443336 PMCID: PMC10914854 DOI: 10.1038/s41467-024-46193-z] [Citation(s) in RCA: 37] [Impact Index Per Article: 37.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2023] [Accepted: 02/14/2024] [Indexed: 03/07/2024] Open
Abstract
Abundant macrophage infiltration and altered tumor metabolism are two key hallmarks of glioblastoma. By screening a cluster of metabolic small-molecule compounds, we show that inhibiting glioblastoma cell glycolysis impairs macrophage migration and lactate dehydrogenase inhibitor stiripentol emerges as the top hit. Combined profiling and functional studies demonstrate that lactate dehydrogenase A (LDHA)-directed extracellular signal-regulated kinase (ERK) pathway activates yes-associated protein 1 (YAP1)/ signal transducer and activator of transcription 3 (STAT3) transcriptional co-activators in glioblastoma cells to upregulate C-C motif chemokine ligand 2 (CCL2) and CCL7, which recruit macrophages into the tumor microenvironment. Reciprocally, infiltrating macrophages produce LDHA-containing extracellular vesicles to promote glioblastoma cell glycolysis, proliferation, and survival. Genetic and pharmacological inhibition of LDHA-mediated tumor-macrophage symbiosis markedly suppresses tumor progression and macrophage infiltration in glioblastoma mouse models. Analysis of tumor and plasma samples of glioblastoma patients confirms that LDHA and its downstream signals are potential biomarkers correlating positively with macrophage density. Thus, LDHA-mediated tumor-macrophage symbiosis provides therapeutic targets for glioblastoma.
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Affiliation(s)
- Fatima Khan
- Department of Neurological Surgery, Lou and Jean Malnati Brain Tumor Institute, Robert H Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago, IL, 60611, USA
| | - Yiyun Lin
- Department of Genetics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
- UTHealth Graduate School of Biomedical Sciences, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Heba Ali
- Department of Neurological Surgery, Lou and Jean Malnati Brain Tumor Institute, Robert H Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago, IL, 60611, USA
| | - Lizhi Pang
- Department of Neurological Surgery, Lou and Jean Malnati Brain Tumor Institute, Robert H Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago, IL, 60611, USA
| | - Madeline Dunterman
- Department of Neurological Surgery, Lou and Jean Malnati Brain Tumor Institute, Robert H Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago, IL, 60611, USA
| | - Wen-Hao Hsu
- UTHealth Graduate School of Biomedical Sciences, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
- Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77054, USA
| | - Katie Frenis
- Department of Hematology, Boston Children's Hospital, Boston, MA, 02115, USA
- Harvard Medical School, Boston, MA, 02115, USA
| | - R Grant Rowe
- Department of Hematology, Boston Children's Hospital, Boston, MA, 02115, USA
- Harvard Medical School, Boston, MA, 02115, USA
- Dana-Farber Boston Children's Cancer and Blood Disorders Center, Boston, MA, 02115, USA
| | - Derek A Wainwright
- Department of Neurological Surgery, Lou and Jean Malnati Brain Tumor Institute, Robert H Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago, IL, 60611, USA
| | - Kathleen McCortney
- Department of Neurological Surgery, Lou and Jean Malnati Brain Tumor Institute, Robert H Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago, IL, 60611, USA
| | - Leah K Billingham
- Department of Neurological Surgery, Lou and Jean Malnati Brain Tumor Institute, Robert H Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago, IL, 60611, USA
| | - Jason Miska
- Department of Neurological Surgery, Lou and Jean Malnati Brain Tumor Institute, Robert H Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago, IL, 60611, USA
| | - Craig Horbinski
- Department of Neurological Surgery, Lou and Jean Malnati Brain Tumor Institute, Robert H Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago, IL, 60611, USA
- Department of Pathology, Northwestern University Feinberg School of Medicine, Chicago, IL, 60611, USA
| | - Maciej S Lesniak
- Department of Neurological Surgery, Lou and Jean Malnati Brain Tumor Institute, Robert H Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago, IL, 60611, USA
| | - Peiwen Chen
- Department of Neurological Surgery, Lou and Jean Malnati Brain Tumor Institute, Robert H Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago, IL, 60611, USA.
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15
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Liang W, Liu M, Su Y, Wen Y, Wang L, Shan J, Zhao J, Xie K, Wang J. Spinster homolog 2 reduces malignancies of glioblastoma via PTEN/PI3K/AKT pathway. IUBMB Life 2024; 76:140-160. [PMID: 37728571 DOI: 10.1002/iub.2785] [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: 08/07/2023] [Accepted: 09/01/2023] [Indexed: 09/21/2023]
Abstract
The molecular mechanisms of glioblastoma (GBM) are unclear, and the prognosis is poor. Spinster homolog 2 (SPNS2) is reportedly involved in pathological processes such as immune response, vascular development, and cancer. However, the biological function and molecular role of SPNS2 in GBM are unclear. SPNS2 is aberrantly low expressed in glioma. Survival curves, risk scores, prognostic nomograms, and univariate and multifactorial Cox regression analyses showed that SPNS2 is an independent prognostic indicator significantly associated with glioma progression and prognosis. Cell function assays and in vivo xenograft transplantation were performed that downregulation of SPNS2 promoted GBM cell growth, migration, invasion, epithelial-mesenchymal transition (EMT), anti-apoptosis, drug resistance, and stemness, while overexpression of SPNS2 had the opposite effect. Meanwhile, the functional enrichment and signaling pathways of SPNS2 in the Cancer Genome Atlas (TCGA), Chinese Glioma Genome Atlas (CGGA), and RNA sequencing were analyzed by Gene ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and Gene set enrichment analysis (GSEA). The above results were related to the inhibition of the PTEN/PI3K/AKT pathway by SPNS2. In addition, we predicted that SPNS2 is closely associated with immune infiltration in the tumor microenvironment by four immune algorithms, ESTIMATE, TIMER, CIBERSORT, and QUANTISEQ. In particular, SPNS2 was negatively correlated with the infiltration of most immune cells, immunomodulators, and chemokines. Finally, single-cell sequencing analysis also revealed that SPNS2 was remarkably correlated with macrophages, and downregulation of SPNS2 promotes the expression of M2-like macrophages. This study provides new evidence that SPNS2 inhibits malignant progression, stemness, and immune infiltration of GBM cells through PTEN/PI3K/AKT pathway. SPNS2 may become a new diagnostic indicator and potential immunotherapeutic target for glioma.
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Affiliation(s)
- Weiye Liang
- Department of Neurobiology, School of Medicine, South China University of Technology, Guangzhou, China
| | - Mingkai Liu
- Department of Neurobiology, School of Medicine, South China University of Technology, Guangzhou, China
| | - Yuling Su
- Center for Pancreatic Cancer Research, School of Medicine, South China University of Technology, Guangzhou, China
| | - Yulin Wen
- CAS Key Laboratory of Regenerative Biology, Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine, South China Institute for Stem Cell Biology and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, China
| | - Lili Wang
- Department of Pathology, Affiliated Hospital of Qingdao University, Qingdao, China
| | - Jiajie Shan
- Department of Neurobiology, School of Medicine, South China University of Technology, Guangzhou, China
| | - Jie Zhao
- Department of Neurobiology, School of Medicine, South China University of Technology, Guangzhou, China
| | - Keping Xie
- Center for Pancreatic Cancer Research, School of Medicine, South China University of Technology, Guangzhou, China
| | - Jian Wang
- Department of Neurobiology, School of Medicine, South China University of Technology, Guangzhou, China
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16
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Abstract
Gliomas are a diverse group of primary central nervous system tumors that affect both children and adults. Recent studies have revealed a dynamic cross talk that occurs between glioma cells and components of their microenvironment, including neurons, astrocytes, immune cells, and the extracellular matrix. This cross talk regulates fundamental aspects of glioma development and growth. In this review, we discuss recent discoveries about the impact of these interactions on gliomas and highlight how tumor cells actively remodel their microenvironment to promote disease. These studies provide a better understanding of the interactions in the microenvironment that are important in gliomas, offer insight into the cross talk that occurs, and identify potential therapeutic vulnerabilities that can be utilized to improve clinical outcomes.
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Affiliation(s)
- Maya Anjali Jayaram
- Department of Neurological Surgery, Brain Tumor Center, University of California, San Francisco, California, USA;
| | - Joanna J Phillips
- Department of Neurological Surgery, Brain Tumor Center, University of California, San Francisco, California, USA;
- Division of Neuropathology, Department of Pathology, University of California, San Francisco, California, USA
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17
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Roetzer-Pejrimovsky T, Nenning KH, Kiesel B, Klughammer J, Rajchl M, Baumann B, Langs G, Woehrer A. Deep learning links localized digital pathology phenotypes with transcriptional subtype and patient outcome in glioblastoma. Gigascience 2024; 13:giae057. [PMID: 39185700 PMCID: PMC11345537 DOI: 10.1093/gigascience/giae057] [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: 10/20/2023] [Revised: 05/13/2024] [Accepted: 07/20/2024] [Indexed: 08/27/2024] Open
Abstract
BACKGROUND Deep learning has revolutionized medical image analysis in cancer pathology, where it had a substantial clinical impact by supporting the diagnosis and prognostic rating of cancer. Among the first available digital resources in the field of brain cancer is glioblastoma, the most common and fatal brain cancer. At the histologic level, glioblastoma is characterized by abundant phenotypic variability that is poorly linked with patient prognosis. At the transcriptional level, 3 molecular subtypes are distinguished with mesenchymal-subtype tumors being associated with increased immune cell infiltration and worse outcome. RESULTS We address genotype-phenotype correlations by applying an Xception convolutional neural network to a discovery set of 276 digital hematozylin and eosin (H&E) slides with molecular subtype annotation and an independent The Cancer Genome Atlas-based validation cohort of 178 cases. Using this approach, we achieve high accuracy in H&E-based mapping of molecular subtypes (area under the curve for classical, mesenchymal, and proneural = 0.84, 0.81, and 0.71, respectively; P < 0.001) and regions associated with worse outcome (univariable survival model P < 0.001, multivariable P = 0.01). The latter were characterized by higher tumor cell density (P < 0.001), phenotypic variability of tumor cells (P < 0.001), and decreased T-cell infiltration (P = 0.017). CONCLUSIONS We modify a well-known convolutional neural network architecture for glioblastoma digital slides to accurately map the spatial distribution of transcriptional subtypes and regions predictive of worse outcome, thereby showcasing the relevance of artificial intelligence-enabled image mining in brain cancer.
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Affiliation(s)
- Thomas Roetzer-Pejrimovsky
- Division of Neuropathology and Neurochemistry, Department of Neurology, Medical University of Vienna, 1090 Vienna, Austria
- Comprehensive Center for Clinical Neurosciences and Mental Health, Medical University of Vienna, 1090 Vienna, Austria
| | - Karl-Heinz Nenning
- Center for Biomedical Imaging and Neuromodulation, Nathan Kline Institute, Orangeburg, NY 10962, USA
- Computational Imaging Research Lab, Department of Biomedical Imaging and Image-guided Therapy, Medical University of Vienna, 1090 Vienna, Austria
| | - Barbara Kiesel
- Department of Neurosurgery, Medical University of Vienna, 1090 Vienna, Austria
| | - Johanna Klughammer
- Gene Center and Department of Biochemistry, Ludwig-Maximilians-Universität München, 80539 Munich, Germany
| | - Martin Rajchl
- Department of Computing and Medicine, Imperial College London, London SW7 2AZ, UK
| | - Bernhard Baumann
- Center for Medical Physics and Biomedical Engineering, Medical University of Vienna, 1090 Vienna, Austria
| | - Georg Langs
- Computational Imaging Research Lab, Department of Biomedical Imaging and Image-guided Therapy, Medical University of Vienna, 1090 Vienna, Austria
| | - Adelheid Woehrer
- Division of Neuropathology and Neurochemistry, Department of Neurology, Medical University of Vienna, 1090 Vienna, Austria
- Comprehensive Center for Clinical Neurosciences and Mental Health, Medical University of Vienna, 1090 Vienna, Austria
- Department of Pathology, Neuropathology and Molecular Pathology, Medical University of Innsbruck, 6020 Innsbruck, Austria
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18
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Lorimer IAJ. Potential roles for efferocytosis in glioblastoma immune evasion. Neurooncol Adv 2024; 6:vdae012. [PMID: 38616895 PMCID: PMC11012614 DOI: 10.1093/noajnl/vdae012] [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] [Subscribe] [Scholar Register] [Indexed: 04/16/2024] Open
Abstract
Glioblastoma is an aggressive and incurable brain cancer. This cancer establishes both local and systemic immunosuppression that creates a major obstacle to effective immunotherapies. Many studies point to tumor-resident myeloid cells (primarily microglia and macrophages) as key mediators of this immunosuppression. Myeloid cells exhibit a high level of plasticity with respect to their phenotype and are capable of both stimulating and repressing immune responses. How glioblastomas recruit myeloid cells and exploit them to avoid the immune system is an active area of research. Macrophages can acquire an immunosuppressive phenotype as a consequence of exposure to cytokines such as TGFB1 or IL4; in addition, macrophages can acquire an immunosuppressive phenotype as a consequence of the engulfment of apoptotic cells, a process referred to as efferocytosis. There is substantial evidence that glioblastoma cells are able to secrete cytokines and other factors that induce an immunosuppressive phenotype in macrophages and microglia. However, less is known about the contribution of efferocytosis to immunosuppression in glioblastoma. Here I review the literature in this area and discuss the potential of efferocytosis inhibition to improve glioblastoma response to immunotherapy.
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Affiliation(s)
- Ian A J Lorimer
- Cancer Research Program, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada
- Department of Medicine, University of Ottawa, Ottawa, Ontario, Canada
- Department of Biochemistry, Microbiology, and Immunology, University of Ottawa, Ottawa, Ontario, Canada
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19
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Nettnin EA, Nguyen T, Arana S, Barros Guinle MI, Garcia CA, Gibson EM, Prolo LM. Review: therapeutic approaches for circadian modulation of the glioma microenvironment. Front Oncol 2023; 13:1295030. [PMID: 38173841 PMCID: PMC10762863 DOI: 10.3389/fonc.2023.1295030] [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: 09/15/2023] [Accepted: 11/28/2023] [Indexed: 01/05/2024] Open
Abstract
High-grade gliomas are malignant brain tumors that are characteristically hard to treat because of their nature; they grow quickly and invasively through the brain tissue and develop chemoradiation resistance in adults. There is also a distinct lack of targeted treatment options in the pediatric population for this tumor type to date. Several approaches to overcome therapeutic resistance have been explored, including targeted therapy to growth pathways (ie. EGFR and VEGF inhibitors), epigenetic modulators, and immunotherapies such as Chimeric Antigen Receptor T-cell and vaccine therapies. One new promising approach relies on the timing of chemotherapy administration based on intrinsic circadian rhythms. Recent work in glioblastoma has demonstrated temporal variations in chemosensitivity and, thus, improved survival based on treatment time of day. This may be due to intrinsic rhythms of the glioma cells, permeability of the blood brain barrier to chemotherapy agents, the tumor immune microenvironment, or another unknown mechanism. We review the literature to discuss chronotherapeutic approaches to high-grade glioma treatment, circadian regulation of the immune system and tumor microenvironment in gliomas. We further discuss how these two areas may be combined to temporally regulate and/or improve the effectiveness of immunotherapies.
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Affiliation(s)
- Ella A. Nettnin
- Department of Neurosurgery, Stanford University School of Medicine, Stanford, CA, United States
| | - Thien Nguyen
- Division of Pediatric Hematology/Oncology, Lucile Packard Children’s Hospital, Palo Alto, CA, United States
| | - Sophia Arana
- Department of Neurosurgery, Stanford University School of Medicine, Stanford, CA, United States
| | | | - Cesar A. Garcia
- Department of Neurosurgery, Stanford University School of Medicine, Stanford, CA, United States
| | - Erin M. Gibson
- Department of Psychiatry and Behavioral Sciences, Stanford University, Stanford, CA, United States
| | - Laura M. Prolo
- Department of Neurosurgery, Stanford University School of Medicine, Stanford, CA, United States
- Division of Pediatric Neurosurgery, Lucile Packard Children’s Hospital, Palo Alto, CA, United States
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20
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du Chatinier A, Velilla IQ, Meel MH, Hoving EW, Hulleman E, Metselaar DS. Microglia in pediatric brain tumors: The missing link to successful immunotherapy. Cell Rep Med 2023; 4:101246. [PMID: 37924816 PMCID: PMC10694606 DOI: 10.1016/j.xcrm.2023.101246] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2023] [Revised: 08/10/2023] [Accepted: 09/26/2023] [Indexed: 11/06/2023]
Abstract
Brain tumors are the leading cause of cancer-related mortality in children. Despite the development of immunotherapeutic strategies for adult brain tumors, progress in pediatric neuro-oncology has been hindered by the complex and poorly understood nature of the brain's immune system during early development, a phase that is critical for the onset of many pediatric brain tumors. A defining characteristic of these tumors is the abundance of microglia, the resident immune cells of the central nervous system. In this review, we explore the concept of microglial diversity across brain regions and throughout development and discuss how their maturation stage may contribute to tumor growth in children. We also summarize the current knowledge on the roles of microglia in common pediatric brain tumor entities and provide examples of myeloid-based immunotherapeutic strategies. Our review underscores the importance of microglial plasticity in pediatric brain tumors and its significance for developing effective immunotherapeutic strategies.
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Affiliation(s)
- Aimée du Chatinier
- Department of Neuro-oncology, Princess Máxima Center for Paediatric Oncology, Heidelberglaan 25, 3584CS Utrecht, the Netherlands
| | - Irene Querol Velilla
- Department of Neuro-oncology, Princess Máxima Center for Paediatric Oncology, Heidelberglaan 25, 3584CS Utrecht, the Netherlands
| | - Michaël Hananja Meel
- Department of Neuro-oncology, Princess Máxima Center for Paediatric Oncology, Heidelberglaan 25, 3584CS Utrecht, the Netherlands
| | - Eelco Wieger Hoving
- Department of Neuro-oncology, Princess Máxima Center for Paediatric Oncology, Heidelberglaan 25, 3584CS Utrecht, the Netherlands
| | - Esther Hulleman
- Department of Neuro-oncology, Princess Máxima Center for Paediatric Oncology, Heidelberglaan 25, 3584CS Utrecht, the Netherlands
| | - Dennis Serge Metselaar
- Department of Neuro-oncology, Princess Máxima Center for Paediatric Oncology, Heidelberglaan 25, 3584CS Utrecht, the Netherlands.
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21
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Silvin A, Qian J, Ginhoux F. Brain macrophage development, diversity and dysregulation in health and disease. Cell Mol Immunol 2023; 20:1277-1289. [PMID: 37365324 PMCID: PMC10616292 DOI: 10.1038/s41423-023-01053-6] [Citation(s) in RCA: 57] [Impact Index Per Article: 28.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2023] [Accepted: 06/01/2023] [Indexed: 06/28/2023] Open
Abstract
Brain macrophages include microglia in the parenchyma, border-associated macrophages in the meningeal-choroid plexus-perivascular space, and monocyte-derived macrophages that infiltrate the brain under various disease conditions. The vast heterogeneity of these cells has been elucidated over the last decade using revolutionary multiomics technologies. As such, we can now start to define these various macrophage populations according to their ontogeny and their diverse functional programs during brain development, homeostasis and disease pathogenesis. In this review, we first outline the critical roles played by brain macrophages during development and healthy aging. We then discuss how brain macrophages might undergo reprogramming and contribute to neurodegenerative disorders, autoimmune diseases, and glioma. Finally, we speculate about the most recent and ongoing discoveries that are prompting translational attempts to leverage brain macrophages as prognostic markers or therapeutic targets for diseases that affect the brain.
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Affiliation(s)
- Aymeric Silvin
- INSERM U1015, Gustave Roussy Cancer Campus, Villejuif, 94800, France
| | - Jiawen Qian
- Shanghai Institute of Immunology, Department of Immunology and Microbiology, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China
| | - Florent Ginhoux
- INSERM U1015, Gustave Roussy Cancer Campus, Villejuif, 94800, France.
- Shanghai Institute of Immunology, Department of Immunology and Microbiology, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China.
- Singapore Immunology Network, Agency for Science, Technology and Research, Singapore, 138648, Republic of Singapore.
- Translational Immunology Institute, SingHealth Duke-NUS Academic Medical Centre, Singapore, 169856, Singapore.
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22
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Messiaen J, Jacobs SA, De Smet F. The tumor micro-environment in pediatric glioma: friend or foe? Front Immunol 2023; 14:1227126. [PMID: 37901250 PMCID: PMC10611473 DOI: 10.3389/fimmu.2023.1227126] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2023] [Accepted: 09/27/2023] [Indexed: 10/31/2023] Open
Abstract
Brain tumors are the leading cause of morbidity and mortality related to cancer in children, where high-grade glioma harbor the worst prognosis. It has become obvious that pediatric glioma differs significantly from their adult counterparts, rendering extrapolations difficult. Curative options for several types of glioma are lacking, albeit ongoing research efforts and clinical trials. As already proven in the past, inter- and intratumoral heterogeneity plays an important role in the resistance to therapy and thus implicates morbidity and mortality for these patients. However, while less studied, the tumor micro-environment (TME) adds another level of heterogeneity. Knowledge gaps exist on how the TME interacts with the tumor cells and how the location of the various cell types in the TME influences tumor growth and the response to treatment. Some studies identified the presence of several (immune) cell types as prognostic factors, but often lack a deeper understanding of the underlying mechanisms, possibly leading to contradictory findings. Although the TME in pediatric glioma is regarded as "cold", several treatment options are emerging, with the TME being the primary target of treatment. Therefore, it is crucial to study the TME of pediatric glioma, so that the interactions between TME, tumoral cells and therapeutics can be better understood before, during and after treatment. In this review, we provide an overview of the available insights into the composition and role of the TME across different types of pediatric glioma. Moreover, where possible, we provide a framework on how a particular TME may influence responses to conventional- and/or immunotherapy.
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Affiliation(s)
- Julie Messiaen
- Department of Pediatrics, University Hospitals Leuven, Leuven, Belgium
- Laboratory for Precision Cancer Medicine, Translational Cell and Tissue Research, Department of Imaging and Pathology, KU Leuven, Leuven, Belgium
| | - Sandra A. Jacobs
- Department of Pediatrics, University Hospitals Leuven, Leuven, Belgium
- Pediatric Oncology, Department of Oncology, KU Leuven, Leuven, Belgium
| | - Frederik De Smet
- Laboratory for Precision Cancer Medicine, Translational Cell and Tissue Research, Department of Imaging and Pathology, KU Leuven, Leuven, Belgium
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23
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Khan F, Lin Y, Ali H, Pang L, Dunterman M, Hsu WH, Frenis K, Rowe RG, Wainwright D, McCortney K, Billingham L, Miska J, Horbinski C, Lesniak M, Chen P. LDHA-regulated tumor-macrophage symbiosis promotes glioblastoma progression. RESEARCH SQUARE 2023:rs.3.rs-3401154. [PMID: 37886538 PMCID: PMC10602051 DOI: 10.21203/rs.3.rs-3401154/v1] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/28/2023]
Abstract
Abundant macrophage infiltration and altered tumor metabolism are two key hallmarks of glioblastoma. By screening a cluster of metabolic small-molecule compounds, we show that inhibiting glioblastoma cell glycolysis impairs macrophage migration and lactate dehydrogenase (LDH) inhibitor stiripentol (an FDA-approved anti-seizure drug for Dravet Syndrome) emerges as the top hit. Combined profiling and functional studies demonstrate that LDHA-directed ERK pathway activates YAP1/STAT3 transcriptional co-activators in glioblastoma cells to upregulate CCL2 and CCL7, which recruit macrophages into the tumor microenvironment. Reciprocally, infiltrating macrophages produce LDHA-containing extracellular vesicles to promote glioblastoma cell glycolysis, proliferation, and survival. Genetic and pharmacological inhibition of LDHA-mediated tumor-macrophage symbiosis markedly suppresses tumor progression and macrophage infiltration in glioblastoma mouse models. Analysis of tumor and plasma samples of glioblastoma patients confirms that LDHA and its downstream signals are potential biomarkers correlating positively with macrophage density. Thus, LDHA-mediated tumor-macrophage symbiosis provides therapeutic targets for glioblastoma.
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Affiliation(s)
| | - Yiyu Lin
- Department of Genetics, The University of Texas MD Anderson Cancer Center
| | - Heba Ali
- Department of Genetics, The University of Texas MD Anderson Cancer Center
| | - Lizhi Pang
- Feinberg School of Medicine, Northwestern University
| | | | - Wen-Hao Hsu
- Department of Cancer Biology, The University of Texas MD Anderson Cancer Center
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24
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Ly KI, Richardson LG, Liu M, Muzikansky A, Cardona J, Lou K, Beers AL, Chang K, Brown JM, Ma X, Reardon DA, Arrillaga-Romany IC, Forst DA, Jordan JT, Lee EQ, Dietrich J, Nayak L, Wen PY, Chukwueke U, Giobbie-Hurder A, Choi BD, Batchelor TT, Kalpathy-Cramer J, Curry WT, Gerstner ER. Bavituximab Decreases Immunosuppressive Myeloid-Derived Suppressor Cells in Newly Diagnosed Glioblastoma Patients. Clin Cancer Res 2023; 29:3017-3025. [PMID: 37327319 DOI: 10.1158/1078-0432.ccr-23-0203] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2023] [Revised: 03/29/2023] [Accepted: 06/13/2023] [Indexed: 06/18/2023]
Abstract
PURPOSE We evaluated the efficacy of bavituximab-a mAb with anti-angiogenic and immunomodulatory properties-in newly diagnosed patients with glioblastoma (GBM) who also received radiotherapy and temozolomide. Perfusion MRI and myeloid-related gene transcription and inflammatory infiltrates in pre-and post-treatment tumor specimens were studied to evaluate on-target effects (NCT03139916). PATIENTS AND METHODS Thirty-three adults with IDH--wild-type GBM received 6 weeks of concurrent chemoradiotherapy, followed by 6 cycles of temozolomide (C1-C6). Bavituximab was given weekly, starting week 1 of chemoradiotherapy, for at least 18 weeks. The primary endpoint was proportion of patients alive at 12 months (OS-12). The null hypothesis would be rejected if OS-12 was ≥72%. Relative cerebral blood flow (rCBF) and vascular permeability (Ktrans) were calculated from perfusion MRIs. Peripheral blood mononuclear cells and tumor tissue were analyzed pre-treatment and at disease progression using RNA transcriptomics and multispectral immunofluorescence for myeloid-derived suppressor cells (MDSC) and macrophages. RESULTS The study met its primary endpoint with an OS-12 of 73% (95% confidence interval, 59%-90%). Decreased pre-C1 rCBF (HR, 4.63; P = 0.029) and increased pre-C1 Ktrans were associated with improved overall survival (HR, 0.09; P = 0.005). Pre-treatment overexpression of myeloid-related genes in tumor tissue was associated with longer survival. Post-treatment tumor specimens contained fewer immunosuppressive MDSCs (P = 0.01). CONCLUSIONS Bavituximab has activity in newly diagnosed GBM and resulted in on-target depletion of intratumoral immunosuppressive MDSCs. Elevated pre-treatment expression of myeloid-related transcripts in GBM may predict response to bavituximab.
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Affiliation(s)
- K Ina Ly
- Stephen E. and Catherine Pappas Center for Neuro-Oncology Massachusetts General Hospital Cancer Center, Boston, Massachusetts
| | - Leland G Richardson
- Department of Neurosurgery Massachusetts General Hospital, Boston, Massachusetts
| | - Mofei Liu
- Division of Biostatistics, Department of Data Sciences, Dana-Farber Cancer Institute, Boston, Massachusetts
| | - Alona Muzikansky
- Department of Biostatistics Massachusetts General Hospital Cancer Center, Boston, Massachusetts
| | - Jonathan Cardona
- Athinoula A. Martinos Center for Biomedical Imaging, Massachusetts General Hospital, Boston, Massachusetts
| | - Kevin Lou
- Athinoula A. Martinos Center for Biomedical Imaging, Massachusetts General Hospital, Boston, Massachusetts
| | - Andrew L Beers
- Athinoula A. Martinos Center for Biomedical Imaging, Massachusetts General Hospital, Boston, Massachusetts
| | - Ken Chang
- Athinoula A. Martinos Center for Biomedical Imaging, Massachusetts General Hospital, Boston, Massachusetts
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York
| | - James M Brown
- Athinoula A. Martinos Center for Biomedical Imaging, Massachusetts General Hospital, Boston, Massachusetts
| | - Xiaoyue Ma
- Athinoula A. Martinos Center for Biomedical Imaging, Massachusetts General Hospital, Boston, Massachusetts
| | - David A Reardon
- Center for Neuro-Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts
| | - Isabel C Arrillaga-Romany
- Stephen E. and Catherine Pappas Center for Neuro-Oncology Massachusetts General Hospital Cancer Center, Boston, Massachusetts
| | - Deborah A Forst
- Stephen E. and Catherine Pappas Center for Neuro-Oncology Massachusetts General Hospital Cancer Center, Boston, Massachusetts
| | - Justin T Jordan
- Stephen E. and Catherine Pappas Center for Neuro-Oncology Massachusetts General Hospital Cancer Center, Boston, Massachusetts
| | - Eudocia Q Lee
- Center for Neuro-Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts
| | - Jorg Dietrich
- Stephen E. and Catherine Pappas Center for Neuro-Oncology Massachusetts General Hospital Cancer Center, Boston, Massachusetts
| | - Lakshmi Nayak
- Center for Neuro-Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts
| | - Patrick Y Wen
- Center for Neuro-Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts
| | - Ugonma Chukwueke
- Center for Neuro-Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts
| | - Anita Giobbie-Hurder
- Division of Biostatistics, Department of Data Sciences, Dana-Farber Cancer Institute, Boston, Massachusetts
| | - Bryan D Choi
- Department of Neurosurgery Massachusetts General Hospital, Boston, Massachusetts
| | - Tracy T Batchelor
- Department of Neurology, Brigham and Women's Hospital, Boston, Massachusetts
| | - Jayashree Kalpathy-Cramer
- Athinoula A. Martinos Center for Biomedical Imaging, Massachusetts General Hospital, Boston, Massachusetts
| | - William T Curry
- Department of Neurosurgery Massachusetts General Hospital, Boston, Massachusetts
| | - Elizabeth R Gerstner
- Stephen E. and Catherine Pappas Center for Neuro-Oncology Massachusetts General Hospital Cancer Center, Boston, Massachusetts
- Athinoula A. Martinos Center for Biomedical Imaging, Massachusetts General Hospital, Boston, Massachusetts
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25
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Budhiraja S, Najem H, Tripathi S, Wadhawani NR, Horbinski C, McCord M, Lenzen AC, Heimberger AB, DeCuypere M. Immunobiology and Cytokine Modulation of the Pediatric Brain Tumor Microenvironment: A Scoping Review. Cancers (Basel) 2023; 15:3655. [PMID: 37509316 PMCID: PMC10377457 DOI: 10.3390/cancers15143655] [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: 06/02/2023] [Revised: 07/06/2023] [Accepted: 07/13/2023] [Indexed: 07/30/2023] Open
Abstract
Utilizing a Scoping Review strategy in the domain of immune biology to identify immune therapeutic targets, knowledge gaps for implementing immune therapeutic strategies for pediatric brain tumors was assessed. The analysis demonstrated limited efforts to date to characterize and understand the immunological aspects of tumor biology with an over-reliance on observations from the adult glioma population. Foundational knowledge regarding the frequency and ubiquity of immune therapeutic targets is an area of unmet need along with the development of immune-competent pediatric tumor models to test therapeutics and especially combinatorial treatment. Opportunities arise in the evolution of pediatric tumor classification from histological to molecular with targeted immune therapeutics.
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Affiliation(s)
- Shreya Budhiraja
- Division of Pediatric Neurosurgery, Ann and Robert H. Lurie Children’s Hospital of Chicago, Chicago, IL 60611, USA
- Department of Neurological Surgery, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA (C.H.); (A.B.H.)
- Malnati Brain Tumor Institute of the Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA;
| | - Hinda Najem
- Department of Neurological Surgery, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA (C.H.); (A.B.H.)
- Malnati Brain Tumor Institute of the Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA;
| | - Shashwat Tripathi
- Department of Neurological Surgery, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA (C.H.); (A.B.H.)
- Malnati Brain Tumor Institute of the Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA;
| | - Nitin R. Wadhawani
- Division of Pathology, Ann and Robert H. Lurie Children’s Hospital of Chicago, Chicago, IL 60611, USA
| | - Craig Horbinski
- Department of Neurological Surgery, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA (C.H.); (A.B.H.)
- Malnati Brain Tumor Institute of the Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA;
| | - Matthew McCord
- Malnati Brain Tumor Institute of the Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA;
- Department of Pathology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA
| | - Alicia C. Lenzen
- Division of Hematology, Oncology, Neuro-Oncology, and Stem Cell Transplantation, Ann and Robert H. Lurie Children’s Hospital of Chicago, Chicago, IL 60611, USA;
| | - Amy B. Heimberger
- Department of Neurological Surgery, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA (C.H.); (A.B.H.)
- Malnati Brain Tumor Institute of the Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA;
| | - Michael DeCuypere
- Division of Pediatric Neurosurgery, Ann and Robert H. Lurie Children’s Hospital of Chicago, Chicago, IL 60611, USA
- Department of Neurological Surgery, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA (C.H.); (A.B.H.)
- Malnati Brain Tumor Institute of the Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA;
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26
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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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27
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Russo MN, Whaley LA, Norton ES, Zarco N, Guerrero-Cázares H. Extracellular vesicles in the glioblastoma microenvironment: A diagnostic and therapeutic perspective. Mol Aspects Med 2023; 91:101167. [PMID: 36577547 PMCID: PMC10073317 DOI: 10.1016/j.mam.2022.101167] [Citation(s) in RCA: 23] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2022] [Revised: 11/29/2022] [Accepted: 12/12/2022] [Indexed: 12/28/2022]
Abstract
Glioblastoma (GBM), is the most malignant form of gliomas and the most common and lethal primary brain tumor in adults. Conventional cancer treatments have limited to no efficacy on GBM. GBM cells respond and adapt to the surrounding brain parenchyma known as tumor microenvironment (TME) to promote tumor preservation. Among specific TME, there are 3 of particular interest for GBM biology: the perivascular niche, the subventricular zone neurogenic niche, and the immune microenvironment. GBM cells and TME cells present a reciprocal feedback which results in tumor maintenance. One way that these cells can communicate is through extracellular vesicles. These vesicles include exosomes and microvesicles that have the ability to carry both cancerous and non-cancerous cargo, such as miRNA, RNA, proteins, lipids, and DNA. In this review we will discuss the booming topic that is extracellular vesicles, and how they have the novelty to be a diagnostic and targetable vehicle for GBM.
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Affiliation(s)
- Marissa N Russo
- Neurosurgery Department, Mayo Clinic, Jacksonville, FL, USA; Neuroscience Graduate Program, Mayo Clinic Graduate School of Biomedical Sciences, Mayo Clinic, Jacksonville, FL, USA
| | - Lauren A Whaley
- Neurosurgery Department, Mayo Clinic, Jacksonville, FL, USA; Biology Graduate Program, University of North Florida, Jacksonville, FL, USA
| | - Emily S Norton
- Neurosurgery Department, Mayo Clinic, Jacksonville, FL, USA; Neuroscience Graduate Program, Mayo Clinic Graduate School of Biomedical Sciences, Mayo Clinic, Jacksonville, FL, USA; Regenerative Sciences Training Program, Center for Regenerative Medicine, Mayo Clinic, Jacksonville, FL, USA
| | - Natanael Zarco
- Neurosurgery Department, Mayo Clinic, Jacksonville, FL, USA
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28
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Yuile A, Wei JQ, Mohan AA, Hotchkiss KM, Khasraw M. Interdependencies of the Neuronal, Immune and Tumor Microenvironment in Gliomas. Cancers (Basel) 2023; 15:2856. [PMID: 37345193 PMCID: PMC10216320 DOI: 10.3390/cancers15102856] [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: 02/10/2023] [Revised: 05/15/2023] [Accepted: 05/15/2023] [Indexed: 06/23/2023] Open
Abstract
Gliomas are the most common primary brain malignancy and are universally fatal. Despite significant breakthrough in understanding tumor biology, treatment breakthroughs have been limited. There is a growing appreciation that major limitations on effective treatment are related to the unique and highly complex glioma tumor microenvironment (TME). The TME consists of multiple different cell types, broadly categorized into tumoral, immune and non-tumoral, non-immune cells. Each group provides significant influence on the others, generating a pro-tumor dynamic with significant immunosuppression. In addition, glioma cells are highly heterogenous with various molecular distinctions on the cellular level. These variations, in turn, lead to their own unique influence on the TME. To develop future treatments, an understanding of this complex TME interplay is needed. To this end, we describe the TME in adult gliomas through interactions between its various components and through various glioma molecular phenotypes.
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Affiliation(s)
- Alexander Yuile
- Department of Medical Oncology, Royal North Shore Hospital, Reserve Road, St Leonards, NSW 2065, Australia
- The Brain Cancer Group, North Shore Private Hospital, 3 Westbourne Street, St Leonards, NSW 2065, Australia
- Sydney Medical School, Faculty of Medicine and Health Sciences, The University of Sydney, Sydney, NSW 2006, Australia
| | - Joe Q. Wei
- Department of Medical Oncology, Royal North Shore Hospital, Reserve Road, St Leonards, NSW 2065, Australia
- Sydney Medical School, Faculty of Medicine and Health Sciences, The University of Sydney, Sydney, NSW 2006, Australia
| | - Aditya A. Mohan
- The Preston Robert Tisch Brain Tumor Center, Duke University, Durham, NC 27710, USA
| | - Kelly M. Hotchkiss
- The Preston Robert Tisch Brain Tumor Center, Duke University, Durham, NC 27710, USA
| | - Mustafa Khasraw
- The Preston Robert Tisch Brain Tumor Center, Duke University, Durham, NC 27710, USA
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29
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Foss A, Pathania M. Pediatric Glioma Models Provide Insights into Tumor Development and Future Therapeutic Strategies. Dev Neurosci 2023; 46:22-43. [PMID: 37231843 DOI: 10.1159/000531040] [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: 02/20/2023] [Accepted: 05/09/2023] [Indexed: 05/27/2023] Open
Abstract
In depth study of pediatric gliomas has been hampered due to difficulties in accessing patient tissue and a lack of clinically representative tumor models. Over the last decade, however, profiling of carefully curated cohorts of pediatric tumors has identified genetic drivers that molecularly segregate pediatric gliomas from adult gliomas. This information has inspired the development of a new set of powerful in vitro and in vivo tumor models that can aid in identifying pediatric-specific oncogenic mechanisms and tumor microenvironment interactions. Single-cell analyses of both human tumors and these newly developed models have revealed that pediatric gliomas arise from spatiotemporally discrete neural progenitor populations in which developmental programs have become dysregulated. Pediatric high-grade gliomas also harbor distinct sets of co-segregating genetic and epigenetic alterations, often accompanied by unique features within the tumor microenvironment. The development of these novel tools and data resources has led to insights into the biology and heterogeneity of these tumors, including identification of distinctive sets of driver mutations, developmentally restricted cells of origin, recognizable patterns of tumor progression, characteristic immune environments, and tumor hijacking of normal microenvironmental and neural programs. As concerted efforts have broadened our understanding of these tumors, new therapeutic vulnerabilities have been identified, and for the first time, promising new strategies are being evaluated in the preclinical and clinical settings. Even so, dedicated and sustained collaborative efforts are necessary to refine our knowledge and bring these new strategies into general clinical use. In this review, we will discuss the range of currently available glioma models, the way in which they have each contributed to recent developments in the field, their benefits and drawbacks for addressing specific research questions, and their future utility in advancing biological understanding and treatment of pediatric glioma.
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Affiliation(s)
- Amelia Foss
- Department of Oncology and the Milner Institute, Jeffrey Cheah Biomedical Centre, University of Cambridge, Cambridge, UK
- CRUK Children's Brain Tumour Centre of Excellence, University of Cambridge, Cambridge, UK
- Laboratory of Cell Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA
| | - Manav Pathania
- Department of Oncology and the Milner Institute, Jeffrey Cheah Biomedical Centre, University of Cambridge, Cambridge, UK
- CRUK Children's Brain Tumour Centre of Excellence, University of Cambridge, Cambridge, UK
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30
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Kurdi M, Mulla N, Malibary H, Bamaga AK, Fadul MM, Faizo E, Hakamy S, Baeesa S. Immune microenvironment of medulloblastoma: The association between its molecular subgroups and potential targeted immunotherapeutic receptors. World J Clin Oncol 2023; 14:117-130. [PMID: 37009528 PMCID: PMC10052334 DOI: 10.5306/wjco.v14.i3.117] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/14/2022] [Revised: 02/08/2023] [Accepted: 02/22/2023] [Indexed: 03/19/2023] Open
Abstract
Medulloblastoma (MB) is considered the commonest malignant brain tumor in children. Multimodal treatments consisting of surgery, radiation, and chemotherapy have improved patients’ survival. Nevertheless, the recurrence occurs in 30% of cases. The persistent mortality rates, the failure of current therapies to extend life expectancy, and the serious complications of non-targeted cytotoxic treatment indicate the need for more refined therapeutic approaches. Most MBs originating from the neurons of external granular layer line the outer surface of neocerebellum and responsible for the afferent and efferent connections. Recently, MBs have been segregated into four molecular subgroups: Wingless-activated (WNT-MB) (Group 1); Sonic-hedgehog-activated (SHH-MB) (Group 2); Group 3 and 4 MBs. These molecular alterations follow specific gene mutations and disease-risk stratifications. The current treatment protocols and ongoing clinical trials against these molecular subgroups are still using common chemotherapeutic agents by which their efficacy have improved the progression-free survival but did not change the overall survival. However, the need to explore new therapies targeting specific receptors in MB microenvironment became essential. The immune microenvironment of MBs consists of distinctive cellular heterogeneities including immune cells and none-immune cells. Tumour associate macrophage and tumour infiltrating lymphocyte are considered the main principal cells in tumour microenvironment, and their role are still under investigation. In this review, we discuss the mechanism of interaction between MB cells and immune cells in the microenvironment, with an overview of the recent investigations and clinical trials
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Affiliation(s)
- Maher Kurdi
- Department of Pathology, Faculty of Medicine, King Abdulaziz University, Rabigh 213733, Saudi Arabia
- Neuromuscular Unit, King Fahad Medical Research Center, King Abdulaziz University, Jeddah 213733, Saudi Arabia
| | - Nasser Mulla
- Department of Internal Medicine, Faculty of Medicine, Taibah University, Medina 213733, Saudi Arabia
| | - Husam Malibary
- Department of Internal Medicine, Faculty of Medicine, King Abdulaziz University, Jeddah 213733, Saudi Arabia
| | - Ahmed K Bamaga
- Department of Paediatrics, Faculty of Medicine, King Abdulaziz University, Jeddah 213733, Saudi Arabia
| | - Motaz M Fadul
- Department of Pathology, Faculty of Medicine, King Abdulaziz University, Rabigh 213733, Saudi Arabia
| | - Eyad Faizo
- Division of Neurosurgery, Department of Surgery, Faculty of Medicine, Tabuk University, Tabuk 213733, Saudi Arabia
| | - Sahar Hakamy
- Neurmuscular Unit, Center of Excellence of Genomic Medicine, Jeddah 21423, Saudi Arabia
| | - Saleh Baeesa
- Department of Neuroscience, King Faisal Specialist Hospital and Research Center, Jeddah, Saudi Arabia
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31
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Arseni L, Sharma R, Mack N, Nagalla D, Ohl S, Hielscher T, Singhal M, Pilz R, Augustin H, Sandhoff R, Herold-Mende C, Tews B, Lichter P, Seiffert M. Sphingosine-1-Phosphate Recruits Macrophages and Microglia and Induces a Pro-Tumorigenic Phenotype That Favors Glioma Progression. Cancers (Basel) 2023; 15:cancers15020479. [PMID: 36672428 PMCID: PMC9856301 DOI: 10.3390/cancers15020479] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2022] [Revised: 01/05/2023] [Accepted: 01/10/2023] [Indexed: 01/13/2023] Open
Abstract
Glioblastoma is the most aggressive brain tumor in adults. Treatment failure is predominantly caused by its high invasiveness and its ability to induce a supportive microenvironment. As part of this, a major role for tumor-associated macrophages/microglia (TAMs) in glioblastoma development was recognized. Phospholipids are important players in various fundamental biological processes, including tumor-stroma crosstalk, and the bioactive lipid sphingosine-1-phosphate (S1P) has been linked to glioblastoma cell proliferation, invasion, and survival. Despite the urgent need for better therapeutic approaches, novel strategies targeting sphingolipids in glioblastoma are still poorly explored. Here, we showed that higher amounts of S1P secreted by glioma cells are responsible for an active recruitment of TAMs, mediated by S1P receptor (S1PR) signaling through the modulation of Rac1/RhoA. This resulted in increased infiltration of TAMs in the tumor, which, in turn, triggered their pro-tumorigenic phenotype through the inhibition of NFkB-mediated inflammation. Gene set enrichment analyses showed that such an anti-inflammatory microenvironment correlated with shorter survival of glioblastoma patients. Inhibition of S1P restored a pro-inflammatory phenotype in TAMs and resulted in increased survival of tumor-bearing mice. Taken together, our results establish a crucial role for S1P in fine-tuning the crosstalk between glioma and infiltrating TAMs, thus pointing to the S1P-S1PR axis as an attractive target for glioma treatment.
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Affiliation(s)
- Lavinia Arseni
- Division of Molecular Genetics, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany
- Correspondence: (L.A.); (M.S.)
| | - Rakesh Sharma
- Schaller Research Group at the University of Heidelberg and the German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany
- Molecular Mechanisms of Tumor Invasion, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany
- Faculty of Biosciences, Heidelberg University, 69120 Heidelberg, Germany
| | - Norman Mack
- Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 580, 69120 Heidelberg, Germany
| | - Deepthi Nagalla
- Schaller Research Group at the University of Heidelberg and the German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany
- Molecular Mechanisms of Tumor Invasion, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany
| | - Sibylle Ohl
- Division of Molecular Genetics, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany
| | - Thomas Hielscher
- Division of Biostatistics, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany
| | - Mahak Singhal
- European Center for Angioscience (ECAS), Medical Faculty Mannheim, Heidelberg University, 68167 Mannheim, Germany
- Division of Vascular Oncology and Metastasis, German Cancer Research Center (DKFZ)-ZMBH Alliance, 69120 Heidelberg, Germany
| | - Robert Pilz
- Faculty of Biosciences, Heidelberg University, 69120 Heidelberg, Germany
- Lipid Pathobiochemistry, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany
| | - Hellmut Augustin
- European Center for Angioscience (ECAS), Medical Faculty Mannheim, Heidelberg University, 68167 Mannheim, Germany
- Division of Vascular Oncology and Metastasis, German Cancer Research Center (DKFZ)-ZMBH Alliance, 69120 Heidelberg, Germany
| | - Roger Sandhoff
- Lipid Pathobiochemistry, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany
| | - Christel Herold-Mende
- Department of Neurosurgery, Division of Experimental Neurosurgery, Heidelberg University Hospital, 69120 Heidelberg, Germany
| | - Björn Tews
- Schaller Research Group at the University of Heidelberg and the German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany
- Molecular Mechanisms of Tumor Invasion, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany
| | - Peter Lichter
- Division of Molecular Genetics, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany
| | - Martina Seiffert
- Division of Molecular Genetics, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany
- Correspondence: (L.A.); (M.S.)
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Aggarwal P, Luo W, Pehlivan KC, Hoang H, Rajappa P, Cripe TP, Cassady KA, Lee DA, Cairo MS. Pediatric versus adult high grade glioma: Immunotherapeutic and genomic considerations. Front Immunol 2022; 13:1038096. [PMID: 36483545 PMCID: PMC9722734 DOI: 10.3389/fimmu.2022.1038096] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2022] [Accepted: 11/07/2022] [Indexed: 11/23/2022] Open
Abstract
High grade gliomas are identified as malignant central nervous tumors that spread rapidly and have a universally poor prognosis. Historically high grade gliomas in the pediatric population have been treated similarly to adult high grade gliomas. For the first time, the most recent classification of central nervous system tumors by World Health Organization has divided adult from pediatric type diffuse high grade gliomas, underscoring the biologic differences between these tumors in different age groups. The objective of our review is to compare high grade gliomas in the adult versus pediatric patient populations, highlighting similarities and differences in epidemiology, etiology, pathogenesis and therapeutic approaches. High grade gliomas in adults versus children have varying clinical presentations, molecular biology background, and response to chemotherapy, as well as unique molecular targets. However, increasing evidence show that they both respond to recently developed immunotherapies. This review summarizes the distinctions and commonalities between the two in disease pathogenesis and response to therapeutic interventions with a focus on immunotherapy.
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Affiliation(s)
- Payal Aggarwal
- Department of Pediatrics, New York Medical College, Valhalla, NY, United States
| | - Wen Luo
- Department of Pediatrics, New York Medical College, Valhalla, NY, United States,Department of Pathology, Microbiology and Immunology, New York Medical College, Valhalla, NY, United States
| | | | - Hai Hoang
- Department of Pediatrics, New York Medical College, Valhalla, NY, United States
| | - Prajwal Rajappa
- Center for Childhood Cancer Research, Abigail Wexner Research Institute at Nationwide Children’s Hospital, Columbus, OH, United States
| | - Timothy P. Cripe
- Center for Childhood Cancer Research, Abigail Wexner Research Institute at Nationwide Children’s Hospital, Columbus, OH, United States
| | - Kevin A. Cassady
- Center for Childhood Cancer Research, Abigail Wexner Research Institute at Nationwide Children’s Hospital, Columbus, OH, United States
| | - Dean A. Lee
- Center for Childhood Cancer Research, Abigail Wexner Research Institute at Nationwide Children’s Hospital, Columbus, OH, United States
| | - Mitchell S. Cairo
- Department of Pediatrics, New York Medical College, Valhalla, NY, United States,Department of Pathology, Microbiology and Immunology, New York Medical College, Valhalla, NY, United States,Department of Medicine, New York Medical College, Valhalla, NY, United States,Department of Cell Biology and Anatomy, New York Medical College, Valhalla, NY, United States,*Correspondence: Mitchell S. Cairo,
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33
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Silver A, Feier D, Ghosh T, Rahman M, Huang J, Sarkisian MR, Deleyrolle LP. Heterogeneity of glioblastoma stem cells in the context of the immune microenvironment and geospatial organization. Front Oncol 2022; 12:1022716. [PMID: 36338705 PMCID: PMC9628999 DOI: 10.3389/fonc.2022.1022716] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2022] [Accepted: 10/03/2022] [Indexed: 01/16/2023] Open
Abstract
Glioblastoma (GBM) is an extremely aggressive and incurable primary brain tumor with a 10-year survival of just 0.71%. Cancer stem cells (CSCs) are thought to seed GBM's inevitable recurrence by evading standard of care treatment, which combines surgical resection, radiotherapy, and chemotherapy, contributing to this grim prognosis. Effective targeting of CSCs could result in insights into GBM treatment resistance and development of novel treatment paradigms. There is a major ongoing effort to characterize CSCs, understand their interactions with the tumor microenvironment, and identify ways to eliminate them. This review discusses the diversity of CSC lineages present in GBM and how this glioma stem cell (GSC) mosaicism drives global intratumoral heterogeneity constituted by complex and spatially distinct local microenvironments. We review how a tumor's diverse CSC populations orchestrate and interact with the environment, especially the immune landscape. We also discuss how to map this intricate GBM ecosystem through the lens of metabolism and immunology to find vulnerabilities and new ways to disrupt the equilibrium of the system to achieve improved disease outcome.
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Affiliation(s)
- Aryeh Silver
- Department of Neurosurgery, Adam Michael Rosen Neuro-Oncology Laboratories, University of Florida, Gainesville, FL, United States
| | - Diana Feier
- Department of Neurosurgery, Adam Michael Rosen Neuro-Oncology Laboratories, University of Florida, Gainesville, FL, United States
| | - Tanya Ghosh
- Department of Neurosurgery, Adam Michael Rosen Neuro-Oncology Laboratories, University of Florida, Gainesville, FL, United States
| | - Maryam Rahman
- Department of Neurosurgery, Adam Michael Rosen Neuro-Oncology Laboratories, University of Florida, Gainesville, FL, United States,Preston A. Wells, Jr. Center for Brain Tumor Therapy, University of Florida, Gainesville, FL, United States
| | - Jianping Huang
- Department of Neurosurgery, Adam Michael Rosen Neuro-Oncology Laboratories, University of Florida, Gainesville, FL, United States,Preston A. Wells, Jr. Center for Brain Tumor Therapy, University of Florida, Gainesville, FL, United States
| | - Matthew R. Sarkisian
- Preston A. Wells, Jr. Center for Brain Tumor Therapy, University of Florida, Gainesville, FL, United States,Department of Neuroscience, McKnight Brain Institute, University of Florida, Gainesville, FL, United States
| | - Loic P. Deleyrolle
- Department of Neurosurgery, Adam Michael Rosen Neuro-Oncology Laboratories, University of Florida, Gainesville, FL, United States,Preston A. Wells, Jr. Center for Brain Tumor Therapy, University of Florida, Gainesville, FL, United States,*Correspondence: Loic P. Deleyrolle,
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34
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Chen D, Liu Z, Wang J, Yang C, Pan C, Tang Y, Zhang P, Liu N, Li G, Li Y, Wu Z, Xia F, Zhang C, Nie H, Tang Z. Integrative genomic analysis facilitates precision strategies for glioblastoma treatment. iScience 2022; 25:105276. [PMID: 36300002 PMCID: PMC9589211 DOI: 10.1016/j.isci.2022.105276] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2022] [Revised: 08/29/2022] [Accepted: 09/30/2022] [Indexed: 11/13/2022] Open
Abstract
Glioblastoma (GBM) is the most common form of malignant primary brain tumor with a dismal prognosis. Currently, the standard treatments for GBM rarely achieve satisfactory results, which means that current treatments are not individualized and precise enough. In this study, a multiomics-based GBM classification was established and three subclasses (GPA, GPB, and GPC) were identified, which have different molecular features both in bulk samples and at single-cell resolution. A robust GBM poor prognostic signature (GPS) score model was then developed using machine learning method, manifesting an excellent ability to predict the survival of GBM. NVP−BEZ235, GDC−0980, dasatinib and XL765 were ultimately identified to have subclass-specific efficacy targeting patients with a high risk of poor prognosis. Furthermore, the GBM classification and GPS score model could be considered as potential biomarkers for immunotherapy response. In summary, an integrative genomic analysis was conducted to advance individual-based therapies in GBM.
A multiomics-based classification of GBM was established Single-cell transcriptomic profiling of GBM subclasses was revealed using Scissor A robust prognostic risk model was developed for GBM by machine learning method Prediction of potential agents based on molecular and prognostic risk stratification
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Affiliation(s)
- Danyang Chen
- Department of Neurology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Zhicheng Liu
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Jingxuan Wang
- Department of Neurology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Chen Yang
- State Key Laboratory of Oncogenes and Related Genes, Department of Liver Surgery and Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200032, China
| | - Chao Pan
- Department of Neurology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Yingxin Tang
- Department of Neurology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Ping Zhang
- Department of Neurology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Na Liu
- Department of Neurology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Gaigai Li
- Department of Neurology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Yan Li
- State Key Laboratory of Oncogenes and Related Genes, Department of Liver Surgery and Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200032, China,Department of Immunology, Sun Yat-Sen University, Zhongshan School of Medicine, Guangzhou, Guangdong 510080, China
| | - Zhuojin Wu
- Department of Neurology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Feng Xia
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Cuntai Zhang
- Department of Geriatrics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Hao Nie
- Department of Geriatrics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China,Corresponding author
| | - Zhouping Tang
- Department of Neurology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China,Corresponding author
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35
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Shi D, Zhong W, Liu D, Sun X, Hao S, Yang Y, Ao L, Zhou J, Xia Y, Zhou Y, Yu H, Xia H. Computational identification of immune-related lncRNA signature for predicting the prognosis and immune landscape of human glioblastoma multiforme. Front Immunol 2022; 13:932938. [PMID: 36032137 PMCID: PMC9412749 DOI: 10.3389/fimmu.2022.932938] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2022] [Accepted: 07/25/2022] [Indexed: 11/13/2022] Open
Abstract
Emerging evidence shows immune-related long noncoding RNAs (ir-lncRNAs) perform critical roles in tumor progression and prognosis assessment. However, the identification of ir-lncRNAs and their clinical significance in human glioblastoma multiforme (GBM) remain largely unexplored. Here, a designed computational frame based on immune score was used to identify differentially expressed ir-lncRNAs (DEir-lncRNAs) from The Cancer Genome Atlas (TCGA) GBM program. The immune-related lncRNA signature (IRLncSig) composed of prognosis-related DEir-lncRNAs selected by Cox regression analysis and its clinical predictive values were verified, which was further validated by another dataset from the Gene Expression Omnibus database (GEO). Subsequently, the association between IRLncSig and immune cell infiltration, immune checkpoint inhibitor (ICI) biomarkers, O6-methylguanine-DNA methyltransferase (MGMT) gene expression, and biological function were also analyzed. After calculation, five prognosis-related ir-lncRNAs were included in the establishment of IRLncSig. The risk assessment based on IRLncSig indicated that the high-IRLncSig-score group was significantly associated with poor prognosis (p < 0.001), significant aggregation of macrophages (p < 0.05), higher ICI biomarker expression, and MGMT gene expression (p < 0.05). Signature-related lncRNAs may be involved in immune activities in the tumorigenesis and progression of GBM. In summary, the novel IRLncSig shows a promising clinical value in predicting the prognosis and immune landscape of GBM.
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Affiliation(s)
- Dongjie Shi
- Department of Neurosurgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Wenjie Zhong
- Department of Neurosurgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Dan Liu
- Department of Pharmacy, Chongqing General Hospital, University of Chinese Academy of Sciences, Chongqing, China
| | - Xiaochuan Sun
- Department of Neurosurgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Shilei Hao
- Key Laboratory of Biorheological Science and Technology, Ministry of Education, College of Bioengineering, Chongqing University, Chongqing, China
| | - Yaying Yang
- Department of Pathology, Molecular Medicine and Tumor Center, Chongqing Medical University, Chongqing, China
| | - Lei Ao
- Department of Neurosurgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Junjie Zhou
- Department of Pathology, Molecular Medicine and Tumor Center, Chongqing Medical University, Chongqing, China
| | - Yongzhi Xia
- Department of Neurosurgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Yudong Zhou
- Department of Neurosurgery, Children’s Hospital of Chongqing Medical University, Chongqing, China
| | - Hua Yu
- Department of Neurosurgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Haijian Xia
- Department of Neurosurgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
- *Correspondence: Haijian Xia,
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36
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Liang J, Li T, Zhao J, Wang C, Sun H. Current understanding of the human microbiome in glioma. Front Oncol 2022; 12:781741. [PMID: 36003766 PMCID: PMC9393498 DOI: 10.3389/fonc.2022.781741] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2021] [Accepted: 07/11/2022] [Indexed: 11/17/2022] Open
Abstract
There is mounting evidence that the human microbiome is highly associated with a wide variety of central nervous system diseases. However, the link between the human microbiome and glioma is rarely noticed. The exact mechanism of microbiota to affect glioma remains unclear. Recent studies have demonstrated that the microbiome may affect the development, progress, and therapy of gliomas, including the direct impacts of the intratumoral microbiome and its metabolites, and the indirect effects of the gut microbiome and its metabolites. Glioma-related microbiome (gut microbiome and intratumoral microbiome) is associated with both tumor microenvironment and tumor immune microenvironment, which ultimately influence tumorigenesis, progression, and responses to treatment. In this review, we briefly summarize current knowledge regarding the role of the glioma-related microbiome, focusing on its gut microbiome fraction and a brief description of the intratumoral microbiome, and put forward the prospects in which microbiome can be applied in the future and some challenges still need to be solved.
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Affiliation(s)
- Jianhao Liang
- Neurosurgery Center, The National Key Clinical Specialty, The Engineering Technology Research Center of Education Ministry of China on Diagnosis and Treatment of Cerebrovascular Disease, Guangdong Provincial Key Laboratory on Brain Function Repair and Regeneration, The Neurosurgery Institute of Guangdong Province, Zhujiang Hospital, Southern Medical University, Guangzhou, China
| | - Ting Li
- Neurosurgery Center, The National Key Clinical Specialty, The Engineering Technology Research Center of Education Ministry of China on Diagnosis and Treatment of Cerebrovascular Disease, Guangdong Provincial Key Laboratory on Brain Function Repair and Regeneration, The Neurosurgery Institute of Guangdong Province, Zhujiang Hospital, Southern Medical University, Guangzhou, China
| | - Jiajia Zhao
- Neurosurgery Center, The National Key Clinical Specialty, The Engineering Technology Research Center of Education Ministry of China on Diagnosis and Treatment of Cerebrovascular Disease, Guangdong Provincial Key Laboratory on Brain Function Repair and Regeneration, The Neurosurgery Institute of Guangdong Province, Zhujiang Hospital, Southern Medical University, Guangzhou, China
| | - Cheng Wang
- Neurosurgery Center, The National Key Clinical Specialty, The Engineering Technology Research Center of Education Ministry of China on Diagnosis and Treatment of Cerebrovascular Disease, Guangdong Provincial Key Laboratory on Brain Function Repair and Regeneration, The Neurosurgery Institute of Guangdong Province, Zhujiang Hospital, Southern Medical University, Guangzhou, China
| | - Haitao Sun
- Neurosurgery Center, The National Key Clinical Specialty, The Engineering Technology Research Center of Education Ministry of China on Diagnosis and Treatment of Cerebrovascular Disease, Guangdong Provincial Key Laboratory on Brain Function Repair and Regeneration, The Neurosurgery Institute of Guangdong Province, Zhujiang Hospital, Southern Medical University, Guangzhou, China
- Department of Laboratory Medicine, Clinical Biobank Center, Microbiome Medicine Center, Zhujiang Hospital, Southern Medical University, Guangzhou, China
- Key Laboratory of Mental Health of the Ministry of Education, Guangdong-Hong Kong-Macao Greater Bay Area Center for Brain Science and Brain-Inspired Intelligence, Southern Medical University, Guangzhou, China
- *Correspondence: Haitao Sun,
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Zhu H, Ren F, Wang T, Jiang Z, Sun Q, Li Z. Targeted Immunoimaging of Tumor-Associated Macrophages in Orthotopic Glioblastoma by the NIR-IIb Nanoprobes. SMALL (WEINHEIM AN DER BERGSTRASSE, GERMANY) 2022; 18:e2202201. [PMID: 35771091 DOI: 10.1002/smll.202202201] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/08/2022] [Revised: 06/10/2022] [Indexed: 06/15/2023]
Abstract
Developing dynamic and highly sensitive methods for imaging M2-type tumor-associated macrophages (TAMs) is vital for monitoring the tumor progression and assessing the therapeutic efficacy. Here, the fabrication and application of rationally designed Er-based rare-earth nanoprobes for the targeted imaging of M2-type TAMs in glioblastoma (GBM) through the second near-infrared (NIR-II) fluorescence beyond 1500 nm is reported. The NIR-IIb fluorescence of Er-based rare-earth nanoparticles can be remarkably enhanced by optimizing their core-shell structures and the shell thickness, which allows for in vivo imaging under excitation by a 980 nm laser with the lowest power density (40 mW cm-2 ). These bright Er-based nanoparticles functionalized with M2pep polypeptide show notable targeting ability to M2-type macrophages, which has been well tested in both in vitro and in vivo experiments by their up-conversion (UC) fluorescence (540 nm) and down-shifting (DS) fluorescence (1525 nm), respectively. The targeting capability of these nanoprobes in vivo is also demonstrated by the overlap of immunofluorescence of M2-type TAMs and Arsenazo III staining of rare-earth ions in tumor tissue. It is envisioned that these nanoprobes can serve as a companion diagnostic tool to dynamically assess the progression and prognosis of GBM.
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Affiliation(s)
- Hongqin Zhu
- Center for Molecular Imaging and Nuclear Medicine, State Key Laboratory of Radiation Medicine and Protection, School for Radiological and Interdisciplinary Sciences (RAD-X), Collaborative Innovation Center of Radiation Medicine of Jiangsu Higher Education Institutions, Soochow University, Suzhou, 215123, P. R. China
| | - Feng Ren
- Center for Molecular Imaging and Nuclear Medicine, State Key Laboratory of Radiation Medicine and Protection, School for Radiological and Interdisciplinary Sciences (RAD-X), Collaborative Innovation Center of Radiation Medicine of Jiangsu Higher Education Institutions, Soochow University, Suzhou, 215123, P. R. China
| | - Tingting Wang
- Center for Molecular Imaging and Nuclear Medicine, State Key Laboratory of Radiation Medicine and Protection, School for Radiological and Interdisciplinary Sciences (RAD-X), Collaborative Innovation Center of Radiation Medicine of Jiangsu Higher Education Institutions, Soochow University, Suzhou, 215123, P. R. China
| | - Zhilin Jiang
- Center for Molecular Imaging and Nuclear Medicine, State Key Laboratory of Radiation Medicine and Protection, School for Radiological and Interdisciplinary Sciences (RAD-X), Collaborative Innovation Center of Radiation Medicine of Jiangsu Higher Education Institutions, Soochow University, Suzhou, 215123, P. R. China
| | - Qiao Sun
- Center for Molecular Imaging and Nuclear Medicine, State Key Laboratory of Radiation Medicine and Protection, School for Radiological and Interdisciplinary Sciences (RAD-X), Collaborative Innovation Center of Radiation Medicine of Jiangsu Higher Education Institutions, Soochow University, Suzhou, 215123, P. R. China
| | - Zhen Li
- Center for Molecular Imaging and Nuclear Medicine, State Key Laboratory of Radiation Medicine and Protection, School for Radiological and Interdisciplinary Sciences (RAD-X), Collaborative Innovation Center of Radiation Medicine of Jiangsu Higher Education Institutions, Soochow University, Suzhou, 215123, P. R. China
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Antonucci L, Canciani G, Mastronuzzi A, Carai A, Del Baldo G, Del Bufalo F. CAR-T Therapy for Pediatric High-Grade Gliomas: Peculiarities, Current Investigations and Future Strategies. Front Immunol 2022; 13:867154. [PMID: 35603195 PMCID: PMC9115105 DOI: 10.3389/fimmu.2022.867154] [Citation(s) in RCA: 21] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2022] [Accepted: 04/11/2022] [Indexed: 12/15/2022] Open
Abstract
High-Grade Gliomas (HGG) are among the deadliest malignant tumors of central nervous system (CNS) in pediatrics. Despite aggressive multimodal treatment - including surgical resection, radiotherapy and chemotherapy - long-term prognosis of patients remains dismal with a 5-year survival rate less than 20%. Increased understanding of genetic and epigenetic features of pediatric HGGs (pHGGs) revealed important differences with adult gliomas, which need to be considered in order to identify innovative and more effective therapeutic approaches. Immunotherapy is based on different techniques aimed to redirect the patient own immune system to fight specifically cancer cells. In particular, T-lymphocytes can be genetically modified to express chimeric proteins, known as chimeric antigen receptors (CARs), targeting selected tumor-associated antigens (TAA). Disialoganglioside GD2 (GD-2) and B7-H3 are highly expressed on pHGGs and have been evaluated as possible targets in pediatric clinical trials, in addition to the antigens common to adult glioblastoma – such as interleukin-13 receptor alpha 2 (IL-13α2), human epidermal growth factor receptor 2 (HER-2) and erythropoietin-producing human hepatocellular carcinoma A2 receptor (EphA2). CAR-T therapy has shown promise in preclinical model of pHGGs but failed to achieve the same success obtained for hematological malignancies. Several limitations, including the immunosuppressive tumor microenvironment (TME), the heterogeneity in target antigen expression and the difficulty of accessing the tumor site, impair the efficacy of T-cells. pHGGs display an immunologically cold TME with poor T-cell infiltration and scarce immune surveillance. The secretion of immunosuppressive cytokines (TGF-β, IL-10) and the presence of immune-suppressive cells – like tumor-associated macrophages/microglia (TAMs) and myeloid-derived suppressor cells (MDSCs) - limit the effectiveness of immune system to eradicate tumor cells. Innovative immunotherapeutic strategies are necessary to overcome these hurdles and improve ability of T-cells to eradicate tumor. In this review we describe the distinguishing features of HGGs of the pediatric population and of their TME, with a focus on the most promising CAR-T therapies overcoming these hurdles.
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Affiliation(s)
- Laura Antonucci
- Department of Paediatric Haematology and Oncology, Cell and Gene Therapy, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy
| | - Gabriele Canciani
- Department of Paediatric Haematology and Oncology, Cell and Gene Therapy, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy
| | - Angela Mastronuzzi
- Department of Paediatric Haematology and Oncology, Cell and Gene Therapy, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy
| | - Andrea Carai
- Neurosurgery Unit, Department of Neuroscience and Neurorehabilitation, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy
| | - Giada Del Baldo
- Department of Paediatric Haematology and Oncology, Cell and Gene Therapy, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy
| | - Francesca Del Bufalo
- Department of Paediatric Haematology and Oncology, Cell and Gene Therapy, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy
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Wu J, Shen S, Liu T, Ren X, Zhu C, Liang Q, Cui X, Chen L, Cheng P, Cheng W, Wu A. Chemerin enhances mesenchymal features of glioblastoma by establishing autocrine and paracrine networks in a CMKLR1-dependent manner. Oncogene 2022; 41:3024-3036. [PMID: 35459783 PMCID: PMC9122825 DOI: 10.1038/s41388-022-02295-w] [Citation(s) in RCA: 22] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2021] [Revised: 03/14/2022] [Accepted: 03/23/2022] [Indexed: 11/18/2022]
Abstract
Glioblastoma multiforme (GBM) with mesenchymal features exhibits enhanced chemotherapeutic resistance and results in reduced overall survival. Recent studies have suggested that there is a positive correlation between the GBM mesenchymal status and immune cell infiltration. However, the mechanisms by which GBM acquires its mesenchymal features in a tumor immune microenvironment-dependent manner remains unknown. Here, we uncovered a chemerin-mediated autocrine and paracrine network by which the mesenchymal phenotype of GBM cells is strengthened. We identified chemerin as a prognostic secretory protein mediating the mesenchymal phenotype-promoting network between tumor-associated macrophages (TAMs) and tumor cells in GBM. Mechanistically, chemerin promoted the mesenchymal features of GBM by suppressing the ubiquitin-proteasomal degradation of CMKLR1, a chemerin receptor predominantly expressed on TAMs and partially expressed on GBM cells, thereby enhancing NF-κB pathway activation. Moreover, chemerin was found to be involved in the recruitment of TAMs in the GBM tumor microenvironment. We revealed that chemerin also enhances the mesenchymal phenotype-promoting ability of TAMs and promotes their M2 polarization via a CMKLR1/NF-κB axis, which further exacerbates the mesenchymal features of GBM. Blocking the chemerin/CMKLR1 axis with 2-(α-naphthoyl) ethyltrimethylammonium iodide disrupted the mesenchymal network and suppressed tumor growth in GBM. These results suggest the therapeutic potential of targeting the chemerin/CMKLR1 axis to block the mesenchymal network in GBM.
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Affiliation(s)
- Jianqi Wu
- Department of Neurosurgery, The First Hospital of China Medical University, Shenyang, China
| | - Shuai Shen
- Department of Neurosurgery, The First Hospital of China Medical University, Shenyang, China
| | - Tianqi Liu
- Department of Neurosurgery, The First Hospital of China Medical University, Shenyang, China
| | - Xiufang Ren
- Departement of Pathology, Shengjing Hospital of China Medical University, Shenyang, China
| | - Chen Zhu
- Department of Neurosurgery, The First Hospital of China Medical University, Shenyang, China
| | - Qingyu Liang
- Department of Neurosurgery, The First Hospital of China Medical University, Shenyang, China
| | - Xiao Cui
- Department of Neurosurgery, The First Hospital of China Medical University, Shenyang, 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, China
| | - Wen Cheng
- Department of Neurosurgery, The First Hospital of China Medical University, Shenyang, China.
| | - Anhua Wu
- Department of Neurosurgery, The First Hospital of China Medical University, Shenyang, China.
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Zhao Z, Wang Z, Wu Y, Liao D, Zhao B. Comprehensive analysis of TAMs marker genes in glioma for predicting prognosis and immunotherapy response. Mol Immunol 2022; 144:78-95. [DOI: 10.1016/j.molimm.2022.02.012] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2021] [Revised: 02/05/2022] [Accepted: 02/10/2022] [Indexed: 12/17/2022]
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Otani Y, Yoo JY, Lewis CT, Chao S, Swanner J, Shimizu T, Kang JM, Murphy SA, Rivera-Caraballo K, Hong B, Glorioso JC, Nakashima H, Lawler SE, Banasavadi-Siddegowda Y, Heiss JD, Yan Y, Pei G, Caligiuri MA, Zhao Z, Chiocca EA, Yu J, Kaur B. NOTCH-Induced MDSC Recruitment after oHSV Virotherapy in CNS Cancer Models Modulates Antitumor Immunotherapy. Clin Cancer Res 2022; 28:1460-1473. [PMID: 35022322 PMCID: PMC8976724 DOI: 10.1158/1078-0432.ccr-21-2347] [Citation(s) in RCA: 36] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2021] [Revised: 09/02/2021] [Accepted: 12/30/2021] [Indexed: 11/16/2022]
Abstract
PURPOSE Oncolytic herpes simplex virus-1 (oHSV) infection of brain tumors activates NOTCH, however the consequences of NOTCH on oHSV-induced immunotherapy is largely unknown. Here we evaluated the impact of NOTCH blockade on virus-induced immunotherapy. EXPERIMENTAL DESIGN RNA sequencing (RNA-seq), TCGA data analysis, flow cytometry, Luminex- and ELISA-based assays, brain tumor animal models, and serum analysis of patients with recurrent glioblastoma (GBM) treated with oHSV was used to evaluate the effect of NOTCH signaling on virus-induced immunotherapy. RESULTS TCGA data analysis of patients with grade IV glioma and oHSV treatment of experimental brain tumors in mice showed that NOTCH signaling significantly correlated with a higher myeloid cell infiltration. Immunofluorescence staining and RNA-seq uncovered a significant induction of Jag1 (NOTCH ligand) expression in infiltrating myeloid cells upon oHSV infection. Jag1-expressing macrophages further spread NOTCH activation in the tumor microenvironment (TME). NOTCH-activated macrophages increased the secretion of CCL2, which further amplified myeloid-derived suppressor cells. CCL2 and IL10 induction was also observed in serum of patients with recurrent GBM treated with oHSV (rQnestin34.5; NCT03152318). Pharmacologic blockade of NOTCH signaling rescued the oHSV-induced immunosuppressive TME and activated a CD8-dependent antitumor memory response, resulting in a therapeutic benefit. CONCLUSIONS NOTCH-induced immunosuppressive myeloid cell recruitment limited antitumor immunity. Translationally, these findings support the use of NOTCH inhibition in conjunction with oHSV therapy.
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Affiliation(s)
- Yoshihiro Otani
- Department of Neurosurgery, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, TX
| | - Ji Young Yoo
- Department of Neurosurgery, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, TX
| | - Cole T. Lewis
- Department of Neurosurgery, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, TX
| | - Samantha Chao
- Department of Neurosurgery, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, TX
| | - Jessica Swanner
- Department of Neurosurgery, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, TX
| | - Toshihiko Shimizu
- Department of Neurosurgery, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, TX
| | - Jin Muk Kang
- Department of Neurosurgery, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, TX
| | - Sara A. Murphy
- Department of Neurosurgery, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, TX
| | - Kimberly Rivera-Caraballo
- Department of Neurosurgery, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, TX
| | - Bangxing Hong
- Department of Neurosurgery, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, TX
| | - Joseph C. Glorioso
- Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, Pittsburgh, PA
| | - Hiroshi Nakashima
- Harvey W. Cushing Neuro-Oncology Laboratories (HCNL), Department of Neurosurgery, Harvard Medical School and Brigham and Women’s Hospital, Boston, MA
| | - Sean E. Lawler
- Harvey W. Cushing Neuro-Oncology Laboratories (HCNL), Department of Neurosurgery, Harvard Medical School and Brigham and Women’s Hospital, Boston, MA
| | | | - John D. Heiss
- Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD
| | - Yuanqing Yan
- Department of Neurosurgery, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, TX
| | - Guangsheng Pei
- Center for Precision Health, School of Biomedical Informatics, University of Texas Health Science Center at Houston, Houston, TX
| | | | - Zhongming Zhao
- Center for Precision Health, School of Biomedical Informatics, University of Texas Health Science Center at Houston, Houston, TX
- Human Genetics Center, School of Public Health, University of Texas Health Science Center at Houston, Houston, TX
| | - E. Antonio Chiocca
- Harvey W. Cushing Neuro-Oncology Laboratories (HCNL), Department of Neurosurgery, Harvard Medical School and Brigham and Women’s Hospital, Boston, MA
| | - Jianhua Yu
- City of Hope Medical Center, Duarte, CA, USA
| | - Balveen Kaur
- Department of Neurosurgery, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, TX
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Pediatric glioblastoma: mechanisms of immune evasion and potential therapeutic opportunities. Cancer Immunol Immunother 2022; 71:1813-1822. [PMID: 35020009 DOI: 10.1007/s00262-021-03131-y] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2021] [Accepted: 12/09/2021] [Indexed: 12/13/2022]
Abstract
Pediatric glioblastoma is relatively rare compared with its adult counterpart but is associated with a similarly grim prognosis. Available data indicate that pediatric glioblastomas are molecularly distinct from adult tumors, and relatively little is known about the pediatric glioblastoma tumor microenvironment (TME). Cancer immunotherapy has emerged as a new pillar of cancer treatment and is revolutionizing the care of patients with many advanced solid tumors, including melanoma, non-small cell lung cancer, head and neck cancer, and renal cell carcinoma. Unfortunately, attempts to treat adult glioblastoma with current immunotherapies have had limited success to date. Nevertheless, the immune milieu in pediatric glioblastoma is distinct from that found in adult tumors, and evidence suggests that pediatric tumors are less immunosuppressive. As a result, immunotherapies should be specifically evaluated in the pediatric context. The purpose of this review is to explore known and emerging mechanisms of immune evasion in pediatric glioblastoma and highlight potential opportunities for implementing immunotherapy in the treatment of these devastating pediatric brain tumors.
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Yoo K, Kang J, Choi M, Suh Y, Zhao Y, Kim M, Chang JH, Shim J, Yoon S, Kang S, Lee S. Soluble ICAM-1 a Pivotal Communicator between Tumors and Macrophages, Promotes Mesenchymal Shift of Glioblastoma. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2022; 9:e2102768. [PMID: 34813169 PMCID: PMC8805565 DOI: 10.1002/advs.202102768] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 06/29/2021] [Revised: 10/18/2021] [Indexed: 06/13/2023]
Abstract
Despite aggressive clinical treatment, recurrence of glioblastoma multiforme (GBM) is unavoidable, and the clinical outcome is still poor. A convincing explanation is the phenotypic transition of GBM cells upon aggressive treatment such as radiotherapy. However, the microenvironmental factors contributing to GBM recurrence after treatment remain unexplored. Here, it is shown that radiation-treated GBM cells produce soluble intercellular adhesion molecule-1 (sICAM-1) which stimulates the infiltration of macrophages, consequently enriching the tumor microenvironment with inflammatory macrophages. Acting as a paracrine factor, tumor-derived sICAM-1 induces macrophages to secrete wingless-type MMTV integration site family, member 3A (WNT3A), which promotes a mesenchymal shift of GBM cells. In addition, blockade of either sICAM-1 or WNT3A diminishes the harmful effect of radiation on tumor progression. Collectively, the findings indicate that cellular crosstalk between GBM and macrophage through sICAM-1-WNT3A oncogenic route is involved in the mesenchymal shift of GBM cells after radiation, and suggest that radiotherapy combined with sICAM-1 targeted inhibition would improve the clinical outcome of GBM patients.
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Affiliation(s)
- Ki‐Chun Yoo
- Department of Life ScienceResearch Institute for Natural SciencesHanyang UniversitySeoul04763Korea
- Department of Lymphoma and MyelomaDivision of Cancer MedicineCenter for Cancer Immunology ResearchThe University of Texas MD Anderson Cancer CenterHoustonTX77030USA
| | - Jae‐Hyeok Kang
- Department of Life ScienceResearch Institute for Natural SciencesHanyang UniversitySeoul04763Korea
| | - Mi‐Young Choi
- Department of Life ScienceResearch Institute for Natural SciencesHanyang UniversitySeoul04763Korea
| | - Yongjoon Suh
- Department of Life ScienceResearch Institute for Natural SciencesHanyang UniversitySeoul04763Korea
| | - Yi Zhao
- Department of Life ScienceResearch Institute for Natural SciencesHanyang UniversitySeoul04763Korea
| | - Min‐Jung Kim
- Laboratory of Radiation Exposure & TherapeuticsNational Radiation Emergency Medical CenterKorea Institute of Radiological and Medical SciencesSeoul01812Korea
| | - Jong Hee Chang
- Department of NeurosurgeryBrain Tumor CenterSeverance HospitalYonsei University College of MedicineSeoul03722Korea
| | - Jin‐Kyoung Shim
- Department of NeurosurgeryBrain Tumor CenterSeverance HospitalYonsei University College of MedicineSeoul03722Korea
| | - Seon‐Jin Yoon
- Department of NeurosurgeryBrain Tumor CenterSeverance HospitalYonsei University College of MedicineSeoul03722Korea
| | - Seok‐Gu Kang
- Department of NeurosurgeryBrain Tumor CenterSeverance HospitalYonsei University College of MedicineSeoul03722Korea
| | - Su‐Jae Lee
- Department of Life ScienceResearch Institute for Natural SciencesHanyang UniversitySeoul04763Korea
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Datsi A, Sorg RV. Dendritic Cell Vaccination of Glioblastoma: Road to Success or Dead End. Front Immunol 2021; 12:770390. [PMID: 34795675 PMCID: PMC8592940 DOI: 10.3389/fimmu.2021.770390] [Citation(s) in RCA: 50] [Impact Index Per Article: 12.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2021] [Accepted: 10/11/2021] [Indexed: 12/11/2022] Open
Abstract
Glioblastomas (GBM) are the most frequent and aggressive malignant primary brain tumor and remains a therapeutic challenge: even after multimodal therapy, median survival of patients is only 15 months. Dendritic cell vaccination (DCV) is an active immunotherapy that aims at inducing an antitumoral immune response. Numerous DCV trials have been performed, vaccinating hundreds of GBM patients and confirming feasibility and safety. Many of these studies reported induction of an antitumoral immune response and indicated improved survival after DCV. However, two controlled randomized trials failed to detect a survival benefit. This raises the question of whether the promising concept of DCV may not hold true or whether we are not yet realizing the full potential of this therapeutic approach. Here, we discuss the results of recent vaccination trials, relevant parameters of the vaccines themselves and of their application, and possible synergies between DCV and other therapeutic approaches targeting the immunosuppressive microenvironment of GBM.
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Affiliation(s)
- Angeliki Datsi
- Institute for Transplantation Diagnostics and Cell Therapeutics, Heinrich-Heine University Hospital, Medical Faculty, Düsseldorf, Germany
| | - Rüdiger V Sorg
- Institute for Transplantation Diagnostics and Cell Therapeutics, Heinrich-Heine University Hospital, Medical Faculty, Düsseldorf, Germany
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Haydar D, Ibañez-Vega J, Krenciute G. T-Cell Immunotherapy for Pediatric High-Grade Gliomas: New Insights to Overcoming Therapeutic Challenges. Front Oncol 2021; 11:718030. [PMID: 34760690 PMCID: PMC8573171 DOI: 10.3389/fonc.2021.718030] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2021] [Accepted: 10/08/2021] [Indexed: 01/06/2023] Open
Abstract
Despite decades of research, pediatric central nervous system (CNS) tumors remain the most debilitating, difficult to treat, and deadliest cancers. Current therapies, including radiation, chemotherapy, and/or surgery, are unable to cure these diseases and are associated with serious adverse effects and long-term impairments. Immunotherapy using chimeric antigen receptor (CAR) T cells has the potential to elucidate therapeutic antitumor immune responses that improve survival without the devastating adverse effects associated with other therapies. Yet, despite the outstanding performance of CAR T cells against hematologic malignancies, they have shown little success targeting brain tumors. This lack of efficacy is due to a scarcity of targetable antigens, interactions with the immune microenvironment, and physical and biological barriers limiting the homing and trafficking of CAR T cells to brain tumors. In this review, we summarize experiences with CAR T-cell therapy for pediatric CNS tumors in preclinical and clinical settings and focus on the current roadblocks and novel strategies to potentially overcome those therapeutic challenges.
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Affiliation(s)
| | | | - Giedre Krenciute
- Department of Bone Marrow Transplantation & Cellular Therapy, St. Jude Children’s Research Hospital, Memphis, TN, United States
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Panitz V, Končarević S, Sadik A, Friedel D, Bausbacher T, Trump S, Farztdinov V, Schulz S, Sievers P, Schmidt S, Jürgenson I, Jung S, Kuhn K, Pflüger I, Sharma S, Wick A, Pfänder P, Selzer S, Vollmuth P, Sahm F, von Deimling A, Heiland I, Hopf C, Schulz-Knappe P, Pike I, Platten M, Wick W, Opitz CA. Tryptophan metabolism is inversely regulated in the tumor and blood of patients with glioblastoma. Am J Cancer Res 2021; 11:9217-9233. [PMID: 34646367 PMCID: PMC8490504 DOI: 10.7150/thno.60679] [Citation(s) in RCA: 30] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2021] [Accepted: 08/06/2021] [Indexed: 12/13/2022] Open
Abstract
Tryptophan (Trp)-catabolic enzymes (TCEs) produce metabolites that activate the aryl hydrocarbon receptor (AHR) and promote tumor progression and immunosuppression in glioblastoma. As therapies targeting TCEs or AHR become available, a better understanding of Trp metabolism is required. Methods: The combination of LC-MS/MS with chemical isobaric labeling enabled the simultaneous quantitative comparison of Trp and its amino group-bearing metabolites in multiple samples. We applied this method to the sera of a cohort of 43 recurrent glioblastoma patients and 43 age- and sex-matched healthy controls. Tumor volumes were measured in MRI data using an artificial neural network-based approach. MALDI MSI visualized Trp and its direct metabolite N-formylkynurenine (FK) in glioblastoma tissue. Analysis of scRNA-seq data was used to detect the presence of Trp metabolism and AHR activity in different cell types in glioblastoma. Results: Compared to healthy controls, glioblastoma patients showed decreased serum Trp levels. Surprisingly, the levels of Trp metabolites were also reduced. The decrease became smaller with more enzymatic steps between Trp and its metabolites, suggesting that Trp availability controls the levels of its systemic metabolites. High tumor volume associated with low systemic metabolite levels and low systemic kynurenine levels associated with worse overall survival. MALDI MSI demonstrated heterogeneity of Trp catabolism across glioblastoma tissues. Analysis of scRNA-seq data revealed that genes involved in Trp metabolism were expressed in almost all the cell types in glioblastoma and that most cell types, in particular macrophages and T cells, exhibited AHR activation. Moreover, high AHR activity associated with reduced overall survival in the glioblastoma TCGA dataset. Conclusion: The novel techniques we developed could support the identification of patients that may benefit from therapies targeting TCEs or AHR activation.
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Jacques FH, Nicholas G, Lorimer IAJ, Sikati Foko V, Prevost J, Dumais N, Milne K, Nelson BH, Woulfe J, Jansen G, Apedaile BE. Avelumab in newly diagnosed glioblastoma. Neurooncol Adv 2021; 3:vdab118. [PMID: 34604752 PMCID: PMC8482788 DOI: 10.1093/noajnl/vdab118] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/04/2023] Open
Abstract
Background Glioblastoma (GBM) is known to use both local and systemic immunosuppressive strategies. One such strategy is the expression of the immune checkpoint protein programmed cell death ligand-1 (PD-L1) by both tumor cells and tumor-associated immune cells. Recent phase III trials using IgG4 antibodies targeting PD-1, the ligand for PD-L1, failed to show any benefit. Avelumab is an IgG1 monoclonal antibody targeting PD-L1. In contrast to the previously tested immune checkpoint inhibitors, it can directly bind tumor cells and immune cells expressing PD-L1 and can induce antibody-dependent cellular cytotoxicity. Methods We conducted a single center, open label, phase II study where avelumab 10 mg/kg IV Q2W was added concurrently to the first monthly temozolomide cycle in patients with newly diagnosed GBM. Immunohistochemical analyses were performed on surgery samples. The primary objective was safety. Secondary objectives were efficacy outcomes according to the immunotherapy Response Assessment in Neuro Oncology criteria, progression free survival (PFS), and overall survival (OS). Exploratory objectives aimed at determining prognostic biomarkers. Results Thirty patients were started on therapy and two were lost to follow-up. Median follow-up time (reverse Kaplan-Meier) was 41.7 months (IQR: 28.3–43.4). Three (10.0%) patients had a related or possibly related treatment emergent adverse event that lead to transient or permanent discontinuation of avelumab. Eight (26.7%) patients had one or more immune-related adverse events, and 8 (26.7%) patients had an infusion-related reaction. The overall response rate was 23.3%, median PFS was 9.7 months, and the median OS was 15.3 months. No pretreatment biomarkers showed any predictive value. Conclusions The addition of avelumab to standard therapy in patients with GBM was not associated with any new safety signal. There was no apparent improvement in OS. Trial Registration NCT03047473 Registered February 9, 2017.
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Affiliation(s)
| | - Garth Nicholas
- Cancer Therapeutics Program, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada.,Department of Medicine, University of Ottawa, Ottawa, Ontario, Canada
| | - Ian A J Lorimer
- Cancer Therapeutics Program, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada.,Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, Ontario, Canada.,Department of Medicine, University of Ottawa, Ottawa, Ontario, Canada
| | | | | | | | - Katy Milne
- Deeley Research Centre, BC Cancer, Victoria, British Columbia, Canada
| | - Brad H Nelson
- Deeley Research Centre, BC Cancer, Victoria, British Columbia, Canada.,Department of Biochemistry and Microbiology, University of Victoria, Victoria, British Columbia, Canada.,Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia,Canada
| | - John Woulfe
- Department of Pathology and Laboratory Medicine, University of Ottawa, Ottawa, Ontario, Canada
| | - Gerard Jansen
- Department of Pathology and Laboratory Medicine, University of Ottawa, Ottawa, Ontario, Canada
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Rivera M, Bander ED, Cisse B. Perspectives on Microglia-Based Immune Therapies Against Glioblastoma. World Neurosurg 2021; 154:228-231. [PMID: 34583500 DOI: 10.1016/j.wneu.2021.06.127] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2021] [Accepted: 06/26/2021] [Indexed: 12/13/2022]
Abstract
Glioblastoma (GBM) is the most aggressive primary tumor of the central nervous system. Despite aggressive multimodal therapy, it has a dismal prognosis. Over the last 20 years, the approach to GBM research and therapy has involved viewing the pathologic condition as a complex organ system with multiple nonneoplastic cells supporting tumor growth directly or through enhancement of the tumor microenvironment. Understanding the immune system effects on glioma growth, invasion, tumor survival, immune suppression, and angiogenesis is critical in immunotherapy target development. In this review, we discuss how the immune system generates a favorable microenvironment, and clinical trials currently underway targeting immune system pathways. Tumor-associated macrophages, particularly the M2 phenotype, are important residents of the tumor microenvironment, promoting tumor growth through paracrine and direct signaling. Clinical trials targeting PD-L-1, CTLA-4, and colony stimulating factor-1 receptor in GBM are currently under investigation. Additionally, several phase I/II clinical trials are underway using vaccines, oncolytic viruses, antibodies, and chimeric antigen receptor T cells targeting glioma cells. Co-opting the immune system as a therapeutic partner against GBM is in early stages of investigation, and the potential use of such approaches as treatment adjuncts is indispensable for combating this highly heterogeneous disease.
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Affiliation(s)
- Maricruz Rivera
- Department of Neurosurgery, NewYork-Presbyterian/Weill Cornell Medicine, New York, New York, USA
| | - Evan D Bander
- Department of Neurosurgery, NewYork-Presbyterian/Weill Cornell Medicine, New York, New York, USA
| | - Babacar Cisse
- Department of Neurosurgery, NewYork-Presbyterian/Weill Cornell Medicine, New York, New York, USA.
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Cui X, Wang Q, Zhou J, Wang Y, Xu C, Tong F, Wang H, Kang C. Single-Cell Transcriptomics of Glioblastoma Reveals a Unique Tumor Microenvironment and Potential Immunotherapeutic Target Against Tumor-Associated Macrophage. Front Oncol 2021; 11:710695. [PMID: 34434898 PMCID: PMC8382282 DOI: 10.3389/fonc.2021.710695] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2021] [Accepted: 07/09/2021] [Indexed: 12/13/2022] Open
Abstract
Background The main immune cells in GBM are tumor-associated macrophages (TAMs). Thus far, the studies investigating the activation status of TAM in GBM are mainly limited to bulk RNA analyses of individual tumor biopsies. The activation states and transcriptional signatures of TAMs in GBM remain poorly characterized. Methods We comprehensively analyzed single-cell RNA-sequencing data, covering a total of 16,201 cells, to clarify the relative proportions of the immune cells infiltrating GBMs. The origin and TAM states in GBM were characterized using the expression profiles of differential marker genes. The vital transcription factors were examined by SCENIC analysis. By comparing the variable gene expression patterns in different clusters and cell types, we identified components and characteristics of TAMs unique to each GBM subtype. Meanwhile, we interrogated the correlation between SPI1 expression and macrophage infiltration in the TCGA-GBM dataset. Results The expression patterns of TMEM119 and MHC-II can be utilized to distinguish the origin and activation states of TAMs. In TCGA-Mixed tumors, almost all TAMs were bone marrow-derived macrophages. The TAMs in TCGA-proneural tumors were characterized by primed microglia. A different composition was observed in TCGA-classical tumors, which were infiltrated by repressed microglia. Our results further identified SPI1 as a crucial regulon and potential immunotherapeutic target important for TAM maturation and polarization in GBM. Conclusions We describe the immune landscape of human GBM at a single-cell level and define a novel categorization scheme for TAMs in GBM. The immunotherapy against SPI1 would reprogram the immune environment of GBM and enhance the treatment effect of conventional chemotherapy drugs.
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Affiliation(s)
- Xiaoteng Cui
- Lab of Neuro-oncology, Tianjin Neurological Institute, Key Laboratory of Post-Neuroinjury Neuro-repair and Regeneration in Central Nervous System, Department of Neurosurgery, Tianjin Medical University General Hospital, Tianjin, China
| | - Qixue Wang
- Lab of Neuro-oncology, Tianjin Neurological Institute, Key Laboratory of Post-Neuroinjury Neuro-repair and Regeneration in Central Nervous System, Department of Neurosurgery, Tianjin Medical University General Hospital, Tianjin, China
| | - Junhu Zhou
- Lab of Neuro-oncology, Tianjin Neurological Institute, Key Laboratory of Post-Neuroinjury Neuro-repair and Regeneration in Central Nervous System, Department of Neurosurgery, Tianjin Medical University General Hospital, Tianjin, China
| | - Yunfei Wang
- Lab of Neuro-oncology, Tianjin Neurological Institute, Key Laboratory of Post-Neuroinjury Neuro-repair and Regeneration in Central Nervous System, Department of Neurosurgery, Tianjin Medical University General Hospital, Tianjin, China
| | - Can Xu
- Department of Neurosurgery, Affiliated Hospital of Hebei University, Baoding, China
| | - Fei Tong
- Lab of Neuro-oncology, Tianjin Neurological Institute, Key Laboratory of Post-Neuroinjury Neuro-repair and Regeneration in Central Nervous System, Department of Neurosurgery, Tianjin Medical University General Hospital, Tianjin, China
| | - Hongjun Wang
- Department of Neurosurgery, The Second Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Chunsheng Kang
- Lab of Neuro-oncology, Tianjin Neurological Institute, Key Laboratory of Post-Neuroinjury Neuro-repair and Regeneration in Central Nervous System, Department of Neurosurgery, Tianjin Medical University General Hospital, Tianjin, China
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50
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Magod P, Mastandrea I, Rousso-Noori L, Agemy L, Shapira G, Shomron N, Friedmann-Morvinski D. Exploring the longitudinal glioma microenvironment landscape uncovers reprogrammed pro-tumorigenic neutrophils in the bone marrow. Cell Rep 2021; 36:109480. [PMID: 34348160 DOI: 10.1016/j.celrep.2021.109480] [Citation(s) in RCA: 33] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2020] [Revised: 03/17/2021] [Accepted: 07/13/2021] [Indexed: 12/13/2022] Open
Abstract
Recent multi-omics studies show different immune tumor microenvironment (TME) compositions in glioblastoma (GBM). However, temporal comprehensive knowledge of the TME from initiation of the disease remains sparse. We use Cre recombinase (Cre)-inducible lentiviral murine GBM models to compare the cellular evolution of the immune TME in tumors initiated from different oncogenic drivers. We show that neutrophils infiltrate early during tumor progression primarily in the mesenchymal GBM model. Depleting neutrophils in vivo at the onset of disease accelerates tumor growth and reduces the median overall survival time of mice. We show that, as a tumor progresses, bone marrow-derived neutrophils are skewed toward a phenotype associated with pro-tumorigenic processes. Our findings suggest that GBM can remotely regulate systemic myeloid differentiation in the bone marrow to generate neutrophils pre-committed to a tumor-supportive phenotype. This work reveals plasticity in the systemic immune host microenvironment, suggesting an additional point of intervention in GBM treatment.
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Affiliation(s)
- Prerna Magod
- The School of Neurobiology, Biochemistry and Biophysics, The George S. Wise Faculty of Life Sciences, Tel Aviv University, Tel Aviv 6997801, Israel
| | - Ignacio Mastandrea
- The School of Neurobiology, Biochemistry and Biophysics, The George S. Wise Faculty of Life Sciences, Tel Aviv University, Tel Aviv 6997801, Israel
| | - Liat Rousso-Noori
- The School of Neurobiology, Biochemistry and Biophysics, The George S. Wise Faculty of Life Sciences, Tel Aviv University, Tel Aviv 6997801, Israel
| | - Lilach Agemy
- Department of Plant and Environmental Sciences, Weizmann Institute of Science, Rehovot, Israel
| | - Guy Shapira
- Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv 6997801, Israel
| | - Noam Shomron
- Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv 6997801, Israel
| | - Dinorah Friedmann-Morvinski
- The School of Neurobiology, Biochemistry and Biophysics, The George S. Wise Faculty of Life Sciences, Tel Aviv University, Tel Aviv 6997801, Israel; Sagol School of Neuroscience, Tel Aviv University, Tel Aviv, Israel.
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