bims-malgli Biomed News
on Biology of malignant gliomas
Issue of 2024–08–18
eleven papers selected by
Oltea Sampetrean, Keio University
  1. Remote Neuroinflammation in Newly Diagnosed Glioblastoma Correlates with Unfavorable Clinical Outcome.
  2. Distinct tumor-TAM interactions in IDH-stratified glioma microenvironments unveiled by single-cell and spatial transcriptomics.
  3. Immune landscape of isocitrate dehydrogenase-stratified primary and recurrent human gliomas.
  4. Protocol for in vitro evaluation of effects of stiffness on patient-derived glioblastoma.
  5. Pediatric glioma immune profiling identifies TIM3 as a therapeutic target in BRAF-Fusion pilocytic astrocytoma.
  6. A real-world observation of patients with glioblastoma treated with a personalized peptide vaccine.
  7. When playing the NK cell therapy card in glioblastoma, you can't beat interleukin-21.
  8. Combination of loco-regional radiotherapy with a TIM-3 aptamer improves survival in diffuse midline glioma models.
  9. Interleukin-21 engineering enhances NK cell activity against glioblastoma via CEBPD.
  10. The Emerging Field of Viroimmunotherapy for Pediatric Brain Tumors.
  11. Macrophage-mediated myelin recycling fuels brain cancer malignancy.
  1. Clin Cancer Res. 2024 Aug 16.
    Remote Neuroinflammation in Newly Diagnosed Glioblastoma Correlates with Unfavorable Clinical Outcome.
    Laura M Bartos, Stefanie Quach, Valerio Zenatti, Sabrina V Kirchleitner, Jens Blobner, Karin Wind-Mark, Zeynep Ilgin Kolabas, Selin Ulukaya, Adrien Holzgreve, Viktoria C Ruf, Lea H Kunze, Sebastian T Kunte, Leonie Hoermann, Marlies Härtel, Ha Eun Park, Mattes Groß, Nicolai Franzmeier, Artem Zatcepin, Adrian Zounek, Lena Kaiser, Markus J Riemenschneider, Robert Perneczky, Boris-Stephan Rauchmann, Sophia Stoecklein, Sibylle Ziegler, Jochen Herms, Ali Ertürk, Joerg C Tonn, Niklas Thon, Louisa von Baumgarten, Matthias Prestel, Sabina Tahirovic, Nathalie L Albert, Matthias Brendel.
       PURPOSE: Current therapy strategies still provide only limited success in the treatment of glioblastoma, the most frequent primary brain tumor in adults. In addition to the characterization of the tumor microenvironment, global changes in brain of patients with glioblastoma have been described. However, the impact and molecular signature of neuroinflammation distant of the primary tumor site have not yet been thoroughly elucidated.
    EXPERIMENTAL DESIGN: We performed translocator protein (TSPO)-PET in patients with newly diagnosed glioblastoma (n=41), astrocytoma WHO grade 2 (n=7) and healthy controls (n=20) and compared TSPO-PET signals of the non-lesion (i.e. contralateral) hemisphere. Back-translation in syngeneic SB28 glioblastoma mice was used to characterize PET alterations on a cellular level. Ultimately, multiplex gene expression analyses served to profile immune cells in remote brain.
    RESULTS: Our study revealed elevated TSPO-PET signals in contralateral hemispheres of patients with newly diagnosed glioblastoma compared to healthy controls. Contralateral TSPO was associated with persisting epileptic seizures and shorter overall survival independent of the tumor phenotype. Back-translation into syngeneic glioblastoma mice pinpointed myeloid cells as the predominant source of contralateral TSPO-PET signal increases and identified a complex immune signature characterized by myeloid cell activation and immunosuppression in distant brain regions.
    CONCLUSIONS: Neuroinflammation within the contralateral hemisphere can be detected with TSPO-PET imaging and associates with poor outcome in patients with newly diagnosed glioblastoma. The molecular signature of remote neuroinflammation promotes the evaluation of immunomodulatory strategies in patients with detrimental whole brain inflammation as reflected by high TSPO expression.
    DOI:  https://doi.org/10.1158/1078-0432.CCR-24-1563
  2. Acta Neuropathol Commun. 2024 Aug 16. 12(1): 133
    Distinct tumor-TAM interactions in IDH-stratified glioma microenvironments unveiled by single-cell and spatial transcriptomics.
    Meysam Motevasseli, Maryam Darvishi, Alireza Khoshnevisan, Mehdi Zeinalizadeh, Hiva Saffar, Shiva Bayat, Ali Najafi, Mohammad Javad Abbaspour, Ali Mamivand, Susan B Olson, Mina Tabrizi.
      Tumor-associated macrophages (TAMs) residing in the tumor microenvironment (TME) are characterized by their pivotal roles in tumor progression, antitumor immunity, and TME remodeling. However, a thorough comparative characterization of tumor-TAM crosstalk across IDH-defined categories of glioma remains elusive, likely contributing to mixed outcomes in clinical trials. We delineated the phenotypic heterogeneity of TAMs across IDH-stratified gliomas. Notably, two TAM subsets with a mesenchymal phenotype were enriched in IDH-WT glioblastoma (GBM) and correlated with poorer patient survival and reduced response to anti-PD-1 immune checkpoint inhibitor (ICI). We proposed SLAMF9 receptor as a potential therapeutic target. Inference of gene regulatory networks identified PPARG, ELK1, and MXI1 as master transcription factors of mesenchymal BMD-TAMs. Our analyses of reciprocal tumor-TAM interactions revealed distinct crosstalk in IDH-WT tumors, including ANXA1-FPR1/3, FN1-ITGAVB1, VEGFA-NRP1, and TNFSF12-TNFRSF12A with known contribution to immunosuppression, tumor proliferation, invasion and TAM recruitment. Spatially resolved transcriptomics further elucidated the architectural organization of highlighted communications. Furthermore, we demonstrated significant upregulation of ANXA1, FN1, NRP1, and TNFRSF12A genes in IDH-WT tumors using bulk RNA-seq and RT-qPCR. Longitudinal expression analysis of candidate genes revealed no difference between primary and recurrent tumors indicating that the interactive network of malignant states with TAMs does not drastically change upon recurrence. Collectively, our study offers insights into the unique cellular composition and communication of TAMs in glioma TME, revealing novel vulnerabilities for therapeutic interventions in IDH-WT GBM.
    Keywords:  Glioblastoma; Immune checkpoint inhibitor; Tumor microenvironment; Tumor-TAM interaction; Tumor-associated macrophage
    DOI:  https://doi.org/10.1186/s40478-024-01837-5
  3. Neuro Oncol. 2024 Aug 10. pii: noae139. [Epub ahead of print]
    Immune landscape of isocitrate dehydrogenase-stratified primary and recurrent human gliomas.
    Pravesh Gupta, Minghao Dang, Shivangi Oberai, Simona Migliozzi, Rakesh Trivedi, Gayatri Kumar, Mekenzie Peshoff, Nancy Milam, Aml Ahmed, Krishna Bojja, Tuan M Tran, Joy Gumin, Carlos Kamiya-Matsuoka, Jason Huse, Kathryn Cox, Jianzhuo Li, Huma Shehwana, Sameer A Sheth, Rodriguez Saxon, Sun Baohua, Brittany Parker-Kerrigan, Atul Maheshwari, Edwin Roger Parra Cuentas, Nicholas E Navin, Amy B Heimberger, Frederick F Lang, Antonio Iavarone, Karen Clise-Dwyer, Linghua Wang, Krishna P Bhat.
       BACKGROUND: Human gliomas are classified using isocitrate dehydrogenase (IDH) status as a prognosticator; however, the influence of genetic differences and treatment effects on ensuing immunity remains unclear.
    METHODS: In this study, we used sequential single-cell transcriptomics on 144,678 and spectral cytometry on over two million immune cells encompassing 48 human gliomas to decipher their immune landscape.
    RESULTS: We identified 22 distinct immune cell types that contribute to glioma immunity. Specifically, brain-resident microglia (MG) were reduced with a concomitant increase in CD8+ T lymphocytes during glioma recurrence independent of IDH status. In contrast, IDH-wild-type-associated patterns, such as an abundance of antigen-presenting cell-like MG and cytotoxic CD8+ T cells, were observed. Beyond elucidating the differences in IDH, relapse, and treatment-associated immunity, we discovered novel inflammatory MG subpopulations expressing granulysin, a cytotoxic peptide, which is otherwise expressed in lymphocytes only. Furthermore, we provide a robust genomic framework for defining macrophage polarization beyond M1/M2 paradigm and reference signatures of glioma-specific tumor immune microenvironment (termed Glio-TIME-36) for deconvoluting transcriptomic datasets.
    CONCLUSIONS: This study provides advanced optics of the human pan-glioma immune contexture as a valuable guide for translational and clinical applications.
    Keywords:  Glioma; isocitrate dehydrogenase; microglia; tumor immune microenvironment
    DOI:  https://doi.org/10.1093/neuonc/noae139
  4. STAR Protoc. 2024 Aug 14. pii: S2666-1667(24)00431-3. [Epub ahead of print]5(3): 103266
    Protocol for in vitro evaluation of effects of stiffness on patient-derived glioblastoma.
    Alireza Sohrabi, Stephanie K Seidlits.
      Glioblastoma (GBM) is the most common and lethal type of primary brain tumor. Physiologically, GBM cells experience a heterogeneous mechanical landscape. Here, we present an in vitro method to study the effects of tissue stiffness on patient-derived GBM that utilizes hyaluronic acid (HA)-based, mechanically tunable scaffolds for three-dimensional (3D) culture of patient-derived GBM spheroids. We describe steps to fabricate and characterize HA-based scaffolds, culture GBM spheroids within 3D hydrogel scaffolds, and prepare cultured cells for a variety of experimental assessments. For complete details on the use and execution of this protocol, please refer to Sohrabi et al.1.
    Keywords:  Cancer; Material sciences; Tissue Engineering
    DOI:  https://doi.org/10.1016/j.xpro.2024.103266
  5. J Clin Invest. 2024 Aug 13. pii: e177413. [Epub ahead of print]
    Pediatric glioma immune profiling identifies TIM3 as a therapeutic target in BRAF-Fusion pilocytic astrocytoma.
    Shashwat Tripathi, Hinda Najem, Corey Dussold, Sebastian Pacheco, Ruochen Du, Moloud Sooreshjani, Lisa A Hurley, James P Chandler, Roger Stupp, Adam M Sonabend, Craig M Horbinski, Rimas V Lukas, Joanne Xiu, Giselle Y López, Theodore P Nicolaides, Valerie Brown, Nitin R Wadhwani, Sandi K Lam, Charles David James, Ganesh Rao, Maria G Castro, Amy B Heimberger, Michael DeCuypere.
      Despite being the leading cause of childhood mortality, pediatric gliomas have been relatively understudied, and the repurposing of immunotherapies has not been successful. Whole transcriptome sequencing, single-cell sequencing, and sequential multiplex immunofluorescence were used to identify an immunotherapy strategy evaluated in multiple preclinical glioma models. MAPK-driven pediatric gliomas have a higher interferon signature relative to other molecular subgroups. Single-cell sequencing identified an activated and cytotoxic microglia population designated MG-Act in BRAF-fused MAPK-activated pilocytic astrocytoma (PA), but not in high-grade gliomas or normal brain. TIM3 is expressed on MG-Act and on the myeloid cells lining the tumor vasculature but not normal brain. TIM3 expression becomes upregulated on immune cells in the PA microenvironment and anti-TIM3 reprograms ex vivo immune cells from human PAs to a pro-inflammatory cytotoxic phenotype. In a genetically engineered murine model of MAPK-driven low-grade gliomas, anti-TIM3 treatment increased median survival over IgG and anti-PD1 treated mice. ScRNA sequencing data during the therapeutic window of anti-TIM3 demonstrates enrichment of the MG-Act population. The therapeutic activity of anti-TIM3 is abrogated in the CX3CR1 microglia knockout background. These data support the use of anti-TIM3 in clinical trials of pediatric low-grade MAPK-driven gliomas.
    Keywords:  Brain cancer; Cancer immunotherapy; Immunology; Oncology
    DOI:  https://doi.org/10.1172/JCI177413
  6. Nat Commun. 2024 Aug 11. 15(1): 6870
    A real-world observation of patients with glioblastoma treated with a personalized peptide vaccine.
    Pauline Latzer, Henning Zelba, Florian Battke, Annekathrin Reinhardt, Borong Shao, Oliver Bartsch, Armin Rabsteyn, Johannes Harter, Martin Schulze, Thomas Okech, Alexander Golf, Christina Kyzirakos-Feger, Simone Kayser, Natalia Pieper, Magdalena Feldhahn, Julian Wünsche, Christian Seitz, Dirk Hadaschik, Claus Garbe, Till-Karsten Hauser, Christian la Fougère, Dirk Biskup, Dawn Brooke, David Parker, Uwe M Martens, Gerald Illerhaus, Deborah T Blumenthal, Ryan Merrell, Luisa Sánchez Lorenzo, Máté Hidvégi, Paula de Robles, Sied Kebir, William W Li, Vincent W Li, Matthew Williams, Alexandra M Miller, Santosh Kesari, Michael Castro, Annick Desjardins, David M Ashley, Henry S Friedman, Patrick Y Wen, Elisabeth C Neil, Fabio M Iwamoto, Bence Sipos, Karsten Geletneky, Lars Zender, Martin Glas, David A Reardon, Saskia Biskup.
      Current treatment outcome of patients with glioblastoma (GBM) remains poor. Following standard therapy, recurrence is universal with limited survival. Tumors from 173 GBM patients are analysed for somatic mutations to generate a personalized peptide vaccine targeting tumor-specific neoantigens. All patients were treated within the scope of an individual healing attempt. Among all vaccinated patients, including 70 treated prior to progression (primary) and 103 treated after progression (recurrent), the median overall survival from first diagnosis is 31.9 months (95% CI: 25.0-36.5). Adverse events are infrequent and are predominantly grade 1 or 2. A vaccine-induced immune response to at least one of the vaccinated peptides is detected in blood samples of 87 of 97 (90%) monitored patients. Vaccine-specific T-cell responses are durable in most patients. Significantly prolonged survival is observed for patients with multiple vaccine-induced T-cell responses (53 months) compared to those with no/low induced responses (27 months; P = 0.03). Altogether, our results highlight that the application of personalized neoantigen-targeting peptide vaccine is feasible and represents a promising potential treatment option for GBM patients.
    DOI:  https://doi.org/10.1038/s41467-024-51315-8
  7. Cancer Cell. 2024 Aug 12. pii: S1535-6108(24)00268-X. [Epub ahead of print]42(8): 1333-1335
    When playing the NK cell therapy card in glioblastoma, you can't beat interleukin-21.
    Nicholas D Huntington.
      Glioblastoma is the most common brain cancer, with a 5-year survival rate of less than 10%. This grim prognosis highlights the urgent need for novel therapeutic approaches. In this issue of Cancer Cell, Shanley et al.1 report an innovative engineering strategy to supercharge NK cell immunity against glioblastoma.
    DOI:  https://doi.org/10.1016/j.ccell.2024.07.003
  8. JCI Insight. 2024 Aug 15. pii: e175257. [Epub ahead of print]
    Combination of loco-regional radiotherapy with a TIM-3 aptamer improves survival in diffuse midline glioma models.
    Iker Ausejo-Mauleon, Naiara Martinez-Velez, Andrea Lacalle, Daniel de la Nava, Javier Cebollero, Helena Villanueva, Noelia Casares, Javier Marco-Sanz, Virginia Laspidea, Oren Becher, Ana Patiño-García, Sara Labiano, Fernando Pastor, Marta M Alonso.
      Pediatric diffuse midline gliomas (DMG) with H3-K27M-altered are aggressive brain tumors that arise during childhood. Despite advances in genomic knowledge and the significant number of clinical trials testing new targeted therapies, patient outcomes are still insufficient. Immune checkpoint blockades with small molecules, such as aptamers, are opening new therapeutic options that represent hope for this orphan disease. Here, we demonstrated that a TIM-3 aptamer as monotherapy increased the immune infiltration and elicited a strong specific immune response with a tendency to improve the overall survival of treated DMG-bearing mice. Importantly, combining TIM-3 Apt with radiotherapy increased the overall median survival and led to long-term survivor mice in two pediatric DMG orthotopic murine models. Interestingly, TIM-3 aptamer administration increased the number of myeloid populations and the pro-inflammatory ratios of CD8: Tregs in the tumor microenvironment as compared to non-treated groups after radiotherapy. Importantly, the depletion of T-cells led to a major loss of the therapeutic effect achieved by the combination. This work uncovers TIM-3 targeting as an immunotherapy approach to improve the radiotherapy outcome in DMGs and offers a strong foundation for propelling a phase I clinical trial using radiotherapy and TIM-3 blockade combination as a treatment for these tumors.
    Keywords:  Brain cancer; Cancer immunotherapy; Oncology; Radiation therapy; Therapeutics
    DOI:  https://doi.org/10.1172/jci.insight.175257
  9. Cancer Cell. 2024 Aug 12. pii: S1535-6108(24)00272-1. [Epub ahead of print]42(8): 1450-1466.e11
    Interleukin-21 engineering enhances NK cell activity against glioblastoma via CEBPD.
    Mayra Shanley, May Daher, Jinzhuang Dou, Sufang Li, Rafet Basar, Hind Rafei, Merve Dede, Joy Gumin, Jezreel Pantaleόn Garcίa, Ana Karen Nunez Cortes, Shan He, Corry M Jones, Sunil Acharya, Natalie W Fowlkes, Donghai Xiong, Sanjay Singh, Hila Shaim, Samantha Claire Hicks, Bin Liu, Abhinav Jain, Mohammad Fayyad Zaman, Qi Miao, Ye Li, Nadima Uprety, Enli Liu, Luis Muniz-Feliciano, Gary M Deyter, Vakul Mohanty, Patrick Zhang, Scott E Evans, Elizabeth J Shpall, Frederick F Lang, Ken Chen, Katayoun Rezvani.
      Glioblastoma (GBM) is an aggressive brain cancer with limited therapeutic options. Natural killer (NK) cells are innate immune cells with strong anti-tumor activity and may offer a promising treatment strategy for GBM. We compared the anti-GBM activity of NK cells engineered to express interleukin (IL)-15 or IL-21. Using multiple in vivo models, IL-21 NK cells were superior to IL-15 NK cells both in terms of safety and long-term anti-tumor activity, with locoregionally administered IL-15 NK cells proving toxic and ineffective at tumor control. IL-21 NK cells displayed a unique chromatin accessibility signature, with CCAAT/enhancer-binding proteins (C/EBP), especially CEBPD, serving as key transcription factors regulating their enhanced function. Deletion of CEBPD resulted in loss of IL-21 NK cell potency while its overexpression increased NK cell long-term cytotoxicity and metabolic fitness. These results suggest that IL-21, through C/EBP transcription factors, drives epigenetic reprogramming of NK cells, enhancing their anti-tumor efficacy against GBM.
    Keywords:  CEBPD; GBM; IL-21; NK cells
    DOI:  https://doi.org/10.1016/j.ccell.2024.07.007
  10. Neuro Oncol. 2024 Aug 16. pii: noae160. [Epub ahead of print]
    The Emerging Field of Viroimmunotherapy for Pediatric Brain Tumors.
    Marc Garcia-Moure, Virginia Laspidea, Sumit Gupta, Andrew G Gillard, Soumen Khatua, Akhila Parthasarathy, Jiasen He, Frederick F Lang, Juan Fueyo, Marta M Alonso, Candelaria Gomez-Manzano.
      Pediatric brain tumors are the most common solid tumors in children. Even to date, with the advances in multimodality therapeutic management, survival outcomes remain dismal in some types of tumors, such as pediatric-type diffuse high-grade gliomas or central nervous system (CNS) embryonal tumors. Failure to understand the complex molecular heterogeneity and the elusive tumor and microenvironment interplay continues to undermine therapeutic efficacy. Developing a strategy that would improve survival for these fatal tumors remains unmet in pediatric neuro-oncology. Oncolytic viruses (OVs) are emerging as a feasible, safe, and promising therapy for brain tumors. The new paradigm in virotherapy implies that the direct cytopathic effect is followed, under certain circumstances, by an antitumor immune response responsible for the partial or complete debulking of the tumor mass. OVs alone or combined with other therapeutic modalities have been primarily used in adult neuro-oncology. A surge in encouraging preclinical studies in pediatric brain tumor models recently led to the clinical translation of OVs with encouraging results in these tumors. In this review, we summarize the different virotherapy tested in preclinical and clinical studies in pediatric brain tumors, and we discuss the limitations and future avenues necessary to improve the response of these tumors to this type of therapy.
    Keywords:  clinical trials; oncolytic viruses; pediatric Brain Tumors; preclinical Studies; viroimmunotherapy
    DOI:  https://doi.org/10.1093/neuonc/noae160
  11. Cell. 2024 Aug 07. pii: S0092-8674(24)00824-9. [Epub ahead of print]
    Macrophage-mediated myelin recycling fuels brain cancer malignancy.
    Daan J Kloosterman, Johanna Erbani, Menno Boon, Martina Farber, Shanna M Handgraaf, Masami Ando-Kuri, Elena Sánchez-López, Bauke Fontein, Marjolijn Mertz, Marja Nieuwland, Ning Qing Liu, Gabriel Forn-Cuni, Nicole N van der Wel, Anita E Grootemaat, Luuk Reinalda, Sander I van Kasteren, Elzo de Wit, Brian Ruffell, Ewa Snaar-Jagalska, Kevin Petrecca, Dieta Brandsma, Alexander Kros, Martin Giera, Leila Akkari.
      Tumors growing in metabolically challenged environments, such as glioblastoma in the brain, are particularly reliant on crosstalk with their tumor microenvironment (TME) to satisfy their high energetic needs. To study the intricacies of this metabolic interplay, we interrogated the heterogeneity of the glioblastoma TME using single-cell and multi-omics analyses and identified metabolically rewired tumor-associated macrophage (TAM) subpopulations with pro-tumorigenic properties. These TAM subsets, termed lipid-laden macrophages (LLMs) to reflect their cholesterol accumulation, are epigenetically rewired, display immunosuppressive features, and are enriched in the aggressive mesenchymal glioblastoma subtype. Engulfment of cholesterol-rich myelin debris endows subsets of TAMs to acquire an LLM phenotype. Subsequently, LLMs directly transfer myelin-derived lipids to cancer cells in an LXR/Abca1-dependent manner, thereby fueling the heightened metabolic demands of mesenchymal glioblastoma. Our work provides an in-depth understanding of the immune-metabolic interplay during glioblastoma progression, thereby laying a framework to unveil targetable metabolic vulnerabilities in glioblastoma.
    Keywords:  cancer immunity; cholesterol; glioblastoma; lipid metabolism; macrophages; myelin recycling; tumor microenvironment
    DOI:  https://doi.org/10.1016/j.cell.2024.07.030
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