bims-malgli Biomed News
on Biology of malignant gliomas
Issue of 2024–03–03
ten papers selected by
Oltea Sampetrean, Keio University
  1. Glioblastoma-infiltrating CD8+ T cells are predominantly a clonally expanded GZMK+ effector population.
  2. Decoding of the surfaceome and endocytome in primary glioblastoma cells identifies potential target antigens in the hypoxic tumor niche.
  3. Lymphatic endothelial-like cells in the glioblastoma tumor niche drive metabolic alterations that promote stem cell proliferation and survival.
  4. Sexual-biased necroinflammation is revealed as a predictor of bevacizumab benefit in Glioblastoma.
  5. Integrating imaging and genomic data for the discovery of distinct glioblastoma subtypes: a joint learning approach.
  6. NOVA1 acts as an oncogenic RNA-binding protein to regulate cholesterol homeostasis in human glioblastoma cells.
  7. Long-term survivors of glioblastoma: Tumor molecular, clinical, and imaging findings.
  8. synNotch-programmed iPSC-derived NK cells usurp TIGIT and CD73 activities for glioblastoma therapy.
  9. Improving long-term outcomes in pediatric low-grade glioma.
  10. Safety and pharmacokinetics of ONC201 (dordaviprone) administered two consecutive days per week in pediatric patients with H3K27M-mutant glioma.
  1. Cancer Discov. 2024 Feb 28.
    Glioblastoma-infiltrating CD8+ T cells are predominantly a clonally expanded GZMK+ effector population.
    Anthony Z Wang, Bryce L Mashimo, Maximilian O Schaettler, Ngima D Sherpa, Lydia A Leavitt, Alexandra J Livingstone, Saad M Khan, Mao Li, Markus I Anzaldua-Campos, Joseph D Bradley, Eric C Leuthardt, Albert H Kim, Joshua L Dowling, Michael R Chicoine, Pamela S Jones, Bryan D Choi, Daniel P Cahill, Bob S Carter, Allegra A Petti, Tanner M Johanns, Gavin P Dunn.
      Recent clinical trials have highlighted the limited efficacy of T cell-based immunotherapy in patients with glioblastoma (GBM). To better understand the characteristics of tumor-infiltrating lymphocytes (TIL) in GBM, we performed cellular indexing of transcriptomes and epitopes by sequencing (CITE-seq) and single-cell RNA sequencing (scRNA-seq) with paired V(D)J sequencing, respectively, on TIL from two cohorts of patients totaling 15 patients with high grade glioma, including GBM or astrocytoma, IDH mutant, grade 4 (G4A). Analysis of the CD8+ TIL landscape reveals an enrichment of clonally expanded GZMK+ effector T cells in the tumor compared to matched blood, which was validated at the protein level. Furthermore, integration with other cancer types highlights the lack of a canonically exhausted CD8+ T cell population in GBM TIL. These data suggest that GZMK+ effector T cells represent an important T cell subset within the GBM microenvironment and which may harbor potential therapeutic implications.
    DOI:  https://doi.org/10.1158/2159-8290.CD-23-0913
  2. Acta Neuropathol Commun. 2024 Feb 27. 12(1): 35
    Decoding of the surfaceome and endocytome in primary glioblastoma cells identifies potential target antigens in the hypoxic tumor niche.
    Kelin Gonçalves de Oliveira, Anna Bång-Rudenstam, Sarah Beyer, Axel Boukredine, Hugo Talbot, Valeria Governa, Maria C Johansson, Ann-Sofie Månsson, Karin Forsberg-Nilsson, Johan Bengzon, Johan Malmström, Charlotte Welinder, Mattias Belting.
      Immunotherapies with antibody-drug-conjugates (ADC) and CAR-T cells, targeted at tumor surface antigens (surfaceome), currently revolutionize clinical oncology. However, target identification warrants a better understanding of the surfaceome and how it is modulated by the tumor microenvironment. Here, we decode the surfaceome and endocytome and its remodeling by hypoxic stress in glioblastoma (GBM), the most common and aggressive brain tumor in adults. We employed a comprehensive approach for global and dynamic profiling of the surfaceome and endocytosed (endocytome) proteins and their regulation by hypoxia in patient-derived GBM cultures. We found a heterogeneous surface-endocytome profile and a divergent response to hypoxia across GBM cultures. We provide a quantitative ranking of more than 600 surface resident and endocytosed proteins, and their regulation by hypoxia, serving as a resource to the cancer research community. As proof-of-concept, the established target antigen CD44 was identified as a commonly and abundantly expressed surface protein with high endocytic activity. Among hypoxia induced proteins, we reveal CXADR, CD47, CD81, BSG, and FXYD6 as potential targets of the stressed GBM niche. We could validate these findings by immunofluorescence analyses in patient tumors and by increased expression in the hypoxic core of GBM spheroids. Selected candidates were finally confronted by treatment studies, showing their high capacity for internalization and ADC delivery. Importantly, we highlight the limited correlation between transcriptomics and proteomics, emphasizing the critical role of membrane protein enrichment strategies and quantitative mass spectrometry. Our findings provide a comprehensive understanding of the surface-endocytome and its remodeling by hypoxia in GBM as a resource for exploration of targets for immunotherapeutic approaches in GBM.
    Keywords:  Glioblastoma; Hypoxia; Immunotherapy; Proteomics; Tumor antigens
    DOI:  https://doi.org/10.1186/s40478-024-01740-z
  3. Neuro Oncol. 2024 Feb 28. pii: noae020. [Epub ahead of print]
    Lymphatic endothelial-like cells in the glioblastoma tumor niche drive metabolic alterations that promote stem cell proliferation and survival.
    Reilly L Kidwell, Manish K Aghi.
      
    DOI:  https://doi.org/10.1093/neuonc/noae020
  4. Neuro Oncol. 2024 Feb 27. pii: noae033. [Epub ahead of print]
    Sexual-biased necroinflammation is revealed as a predictor of bevacizumab benefit in Glioblastoma.
    Sara Hiller-Vallina, Lucia Mondejar-Ruescas, Marta Caamaño-Moreno, Blanca Cómitre-Mariano, Denisse Alcivar-López, Juan M Sepulveda, Aurelio Hernández-Laín, Ángel Pérez-Núñez, Berta Segura-Collar, Ricardo Gargini.
       BACKGROUND: Glioblastoma (GBM) is a highly malignant brain tumor that affects men more often than women. In addition, the former shows a poorer survival prognosis. To date the reason for this sex-specific aggressiveness remains unclear. Therefore, the aim of this study is to investigate tumor processes that explain these sex differences.
    METHODS: This was a retrospective study of GBM patients which was stratified according to sex. Cohort with 73 tumors were analyzed with immunohistochemistry, RNA-seq and RT-qPCR to characterize differences in vascular and immunological profiles. Transcriptomic profiling, GSEA and pathway enrichment analysis were used for discovery molecular pathways predominant in each group. We further investigated the therapeutic effect of Bevacizumab (VEGFA blocking antibody) in retrospective GBM cohort (36 tumors) based on sex differences.
    RESULTS: We found that under hypoxic tumor conditions, two distinct tumor immuno-angiogenic ecosystems develop linked to sex differences and ESR1 expression are generated. One of these subgroups, which includes male patients with low ESR1 expression, is characterized by vascular fragility associated with the appearance of regions of necrosis and high inflammation (called necroinflamed tumors). This male-specific tumor subtype shows high inflammation related to MDSC infiltration. Using this stratification, we identified a possible group of patients who could respond to bevacizumab (BVZ) and revealed a genetic signature that may find clinical applications as a predictor of those who may benefit most from this treatment.
    CONCLUSIONS: This study provides a stratification based on the sexual differences in GBM, which associates the poor prognosis with the presence of immunosuppressive myeloid cells in the necrotic areas. This new stratification could change the current prognosis of GBM and identifies those who respond to BVZ treatment.
    Keywords:  Bevacizumab; Glioblastoma; estrogen receptor; necroinflammation; sex differences
    DOI:  https://doi.org/10.1093/neuonc/noae033
  5. Sci Rep. 2024 02 28. 14(1): 4922
    Integrating imaging and genomic data for the discovery of distinct glioblastoma subtypes: a joint learning approach.
    Jun Guo, Anahita Fathi Kazerooni, Erik Toorens, Hamed Akbari, Fanyang Yu, Chiharu Sako, Elizabeth Mamourian, Russell T Shinohara, Constantinos Koumenis, Stephen J Bagley, Jennifer J D Morrissette, Zev A Binder, Steven Brem, Suyash Mohan, Robert A Lustig, Donald M O'Rourke, Tapan Ganguly, Spyridon Bakas, MacLean P Nasrallah, Christos Davatzikos.
      Glioblastoma is a highly heterogeneous disease, with variations observed at both phenotypical and molecular levels. Personalized therapies would be facilitated by non-invasive in vivo approaches for characterizing this heterogeneity. In this study, we developed unsupervised joint machine learning between radiomic and genomic data, thereby identifying distinct glioblastoma subtypes. A retrospective cohort of 571 IDH-wildtype glioblastoma patients were included in the study, and pre-operative multi-parametric MRI scans and targeted next-generation sequencing (NGS) data were collected. L21-norm minimization was used to select a subset of 12 radiomic features from the MRI scans, and 13 key driver genes from the five main signal pathways most affected in glioblastoma were selected from the genomic data. Subtypes were identified using a joint learning approach called Anchor-based Partial Multi-modal Clustering on both radiomic and genomic modalities. Kaplan-Meier analysis identified three distinct glioblastoma subtypes: high-risk, medium-risk, and low-risk, based on overall survival outcome (p < 0.05, log-rank test; Hazard Ratio = 1.64, 95% CI 1.17-2.31, Cox proportional hazard model on high-risk and low-risk subtypes). The three subtypes displayed different phenotypical and molecular characteristics in terms of imaging histogram, co-occurrence of genes, and correlation between the two modalities. Our findings demonstrate the synergistic value of integrated radiomic signatures and molecular characteristics for glioblastoma subtyping. Joint learning on both modalities can aid in better understanding the molecular basis of phenotypical signatures of glioblastoma, and provide insights into the biological underpinnings of tumor formation and progression.
    DOI:  https://doi.org/10.1038/s41598-024-55072-y
  6. Proc Natl Acad Sci U S A. 2024 Mar 05. 121(10): e2314695121
    NOVA1 acts as an oncogenic RNA-binding protein to regulate cholesterol homeostasis in human glioblastoma cells.
    Yuhki Saito, Yanhong Yang, Misa Saito, Christopher Y Park, Kosuke Funato, Viviane Tabar, Robert B Darnell.
      NOVA1 is a neuronal RNA-binding protein identified as the target antigen of a rare autoimmune disorder associated with cancer and neurological symptoms, termed paraneoplastic opsoclonus-myoclonus ataxia. Despite the strong association between NOVA1 and cancer, it has been unclear how NOVA1 function might contribute to cancer biology. In this study, we find that NOVA1 acts as an oncogenic factor in a GBM (glioblastoma multiforme) cell line established from a patient. Interestingly, NOVA1 and Argonaute (AGO) CLIP identified common 3' untranslated region (UTR) targets, which were down-regulated in NOVA1 knockdown GBM cells, indicating a transcriptome-wide intersection of NOVA1 and AGO-microRNA (miRNA) targets regulation. NOVA1 binding to 3'UTR targets stabilized transcripts including those encoding cholesterol homeostasis related proteins. Selective inhibition of NOVA1-RNA interactions with antisense oligonucleotides disrupted GBM cancer cell fitness. The precision of our GBM CLIP studies point to both mechanism and precise RNA sequence sites to selectively inhibit oncogenic NOVA1-RNA interactions. Taken together, we find that NOVA1 is commonly overexpressed in GBM, where it can antagonize AGO2-miRNA actions and consequently up-regulates cholesterol synthesis, promoting cell viability.
    Keywords:  CLIP; Nova1; RNA-binding protein; cholesterol; glioblastoma
    DOI:  https://doi.org/10.1073/pnas.2314695121
  7. Neurooncol Adv. 2024 Jan-Dec;6(1):6(1): vdae019
    Long-term survivors of glioblastoma: Tumor molecular, clinical, and imaging findings.
    Nicole Briceno, Elizabeth Vera, Edina Komlodi-Pasztor, Zied Abdullaev, Anna Choi, Ewa Grajkowska, Tricia Kunst, Jason Levine, Matthew Lindsley, Kelly Fernandez, Jennifer Reyes, Lisa Boris, Eric Burton, Marissa Panzer, Lily Polskin, Marta Penas-Prado, Tina Pillai, Brett J Theeler, Jing Wu, Kathleen Wall, Antonios Papanicolau-Sengos, Martha Quezado, James Smirniotopoulos, Kenneth Aldape, Terri S Armstrong, Mark R Gilbert.
       Background: Glioblastoma (GBM) is the most aggressive primary brain malignancy with <45% living a year beyond diagnosis. Previously published investigations of long-term survivors (LTS) provided clinical data but rarely incorporated a comprehensive clinical and molecular analysis. Herein, we identify clinical, imaging, molecular, and outcome features for 23 GBM-LTS patients and compare them with a matched cohort of short-term survivors (STS).
    Methods: Molecularly confirmed Isocitrate Dehydrogenase (IDH) wildtype GBM patients living ≥3 years post-diagnosis (NLTS = 23) or <3 years (NSTS = 75) were identified from our Natural History study. Clinical and demographic characteristics were compared. Tumor tissue was analyzed with targeted next generation sequencing (NGS) (NLTS = 23; NSTS = 74) and methylation analysis (NLTS = 18; NSTS = 28). Pre-surgical MRI scans for a subset of LTS (N = 14) and STS control (N = 28) matched on sex, age, and extent of resection were analyzed.
    Results: LTS tended to be younger. Diagnostic MRIs showed more LTS with T1 tumor hypointensity. LTS tumors were enriched for MGMTp methylation and tumor protein 53 (TP53) mutation. Three patients with classic GBM histology were reclassified based on NGS and methylation testing. Additionally, there were LTS with typical poor prognostic molecular markers.
    Conclusions: Our findings emphasize that generalized predictions of prognosis are inaccurate for individual patients and underscore the need for complete clinical evaluation including molecular work-up to confirm the diagnosis. Continued accrual of patients to LTS registries that containcomprehensive clinical, imaging, tumor molecular data, and outcomes measures may pro\vide important insights about individual patient prognosis.
    Keywords:  glioblastoma; long-term survivor; methylation; predictors
    DOI:  https://doi.org/10.1093/noajnl/vdae019
  8. Nat Commun. 2024 Mar 01. 15(1): 1909
    synNotch-programmed iPSC-derived NK cells usurp TIGIT and CD73 activities for glioblastoma therapy.
    Kyle B Lupo, Xue Yao, Shambhavi Borde, Jiao Wang, Sandra Torregrosa-Allen, Bennett D Elzey, Sagar Utturkar, Nadia A Lanman, MacKenzie McIntosh, Sandro Matosevic.
      Severe heterogeneity within glioblastoma has spurred the notion that disrupting the interplay between multiple elements on immunosuppression is at the core of meaningful anti-tumor responses. T cell immunoreceptor with Ig and ITIM domains (TIGIT) and its glioblastoma-associated antigen, CD155, form a highly immunosuppressive axis in glioblastoma and other solid tumors, yet targeting of TIGIT, a functionally heterogeneous receptor on tumor-infiltrating immune cells, has largely been ineffective as monotherapy, suggesting that disruption of its inhibitory network might be necessary for measurable responses. It is within this context that we show that the usurpation of the TIGIT - CD155 axis via engineered synNotch-mediated activation of induced pluripotent stem cell-derived natural killer (NK) cells promotes transcription factor-mediated activation of a downstream signaling cascade that results in the controlled, localized blockade of CD73 to disrupt purinergic activity otherwise resulting in the production and accumulation of immunosuppressive extracellular adenosine. Such "decoy" receptor engages CD155 binding to TIGIT, but tilts inhibitory TIGIT/CD155 interactions toward activation via downstream synNotch signaling. Usurping activities of TIGIT and CD73 promotes the function of adoptively transferred NK cells into intracranial patient-derived models of glioblastoma and enhances their natural cytolytic functions against this tumor to result in complete tumor eradication. In addition, targeting both receptors, in turn, reprograms the glioblastoma microenvironment via the recruitment of T cells and the downregulation of M2 macrophages. This study demonstrates that TIGIT/CD155 and CD73 are targetable receptor partners in glioblastoma. Our data show that synNotch-engineered pluripotent stem cell-derived NK cells are not only effective mediators of anti-glioblastoma responses within the setting of CD73 and TIGIT/CD155 co-targeting, but represent a powerful allogeneic treatment option for this tumor.
    DOI:  https://doi.org/10.1038/s41467-024-46343-3
  9. Nat Cancer. 2024 Mar 01.
    Improving long-term outcomes in pediatric low-grade glioma.
    Johannes Gojo, Matthias Preusser.
      
    DOI:  https://doi.org/10.1038/s43018-024-00741-0
  10. Neuro Oncol. 2024 Feb 24. pii: noae001. [Epub ahead of print]
    Safety and pharmacokinetics of ONC201 (dordaviprone) administered two consecutive days per week in pediatric patients with H3K27M-mutant glioma.
    Yazmin Odia, Carl Koschmann, Nicholas A Vitanza, Peter de Blank, Dolly Aguilera, Jeffrey Allen, Doured Daghistani, Matthew Hall, Ziad Khatib, Cassie Kline, Tobey MacDonald, Sabine Mueller, Shamia L Faison, Joshua E Allen, Odin J Naderer, Samuel C Ramage, Rohinton S Tarapore, Susan Lynne McGovern, Soumen Khatua, Wafik Zaky, Sharon L Gardner.
       BACKGROUND: This study evaluated the safety and pharmacokinetics (PK) of oral ONC201 administered twice-weekly on consecutive days (D1D2) in pediatric patients with newly diagnosed DIPG and/or recurrent/refractory H3 K27M glioma.
    METHODS: This phase 1 dose-escalation and expansion study included pediatric patients with H3 K27M-mutant glioma and/or DIPG following ≥1 line of therapy (NCT03416530). ONC201 was administered D1D2 at three dose levels (DLs; -1, 1, and 2). Actual administered dose within DLs was dependent on weight. Safety was assessed in all DLs; PK analysis was conducted in DL2. Patients receiving once-weekly ONC201 (D1) served as a PK comparator.1.
    RESULTS: Twelve patients received D1D2 ONC201 (DL-1, n=3; DL1, n=3; DL2, n=6); no dose-limiting toxicities or grade ≥3 treatment-related adverse events occurred. PK analyses at DL2 (D1-250mg, n=3; D1-625mg, n=3; D1D2-250mg, n=2; D1D2-625mg, n=2) demonstrated variability in Cmax, AUC0-24, and AUC0-48, with comparable exposures across weight groups. No accumulation occurred with D1D2 dosing; the majority of ONC201 cleared before administration of the second dose. Cmax was variable between groups but did not appear to increase with D1D2 dosing. AUC0-48 was greater with D1D2 than once-weekly.
    CONCLUSIONS: ONC201 given D1D2 was well-tolerated at all DLs and associated with greater AUC0-48.
    Keywords:  H3 K27M mutation; ONC201; dordaviprone; dose optimization
    DOI:  https://doi.org/10.1093/neuonc/noae001
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