bims-malgli Biomed News
on Biology of malignant gliomas
Issue of 2023‒04‒23
nine papers selected by
Oltea Sampetrean
Keio University
  1. Triggering receptor expressed on myeloid cells 2 (TREM2) regulates phagocytosis in glioblastoma.
  2. TREM2 mediates MHCII-associated CD4 + T cell response against gliomas.
  3. Sema3C signaling is an alternative activator of the canonical WNT pathway in glioblastoma.
  4. CD103+ regulatory T cells underlie resistance to radio-immunotherapy and impair CD8+ T cell activation in glioblastoma.
  5. FAM129A promotes self-renewal and maintains invasive status via stabilizing the Notch intracellular domain in glioma stem cells.
  6. Single-Cell Spatial Analysis Identifies Regulators of Brain Tumor-Initiating Cells.
  7. CAR-neutrophil mediated delivery of tumor-microenvironment responsive nanodrugs for glioblastoma chemo-immunotherapy.
  8. Understanding the activity of antibody-drug conjugates in primary and secondary brain tumours.
  9. Cerebrospinal fluid: the new frontier for methylome-based diagnostic classification of brain tumors.
  1. bioRxiv. 2023 Apr 06. pii: 2023.04.05.535792. [Epub ahead of print]
    Triggering receptor expressed on myeloid cells 2 (TREM2) regulates phagocytosis in glioblastoma.
    Mekenzie M Peshoff, Pravesh Gupta, Rakesh Trivedi, Shivangi Oberai, Prashanth Chakrapani, Minghao Dang, Nancy Milam, Mark E Maynard, Brian D Vaillant, Jason T Huse, Linghua Wang, Karen Clise-Dwyer, Krishna P Bhat.
      Glioblastomas (GBMs) are tumors of the central nervous system that remain recalcitrant to both standard of care chemo-radiation and immunotherapies. Emerging approaches to treat GBMs include depletion or re-education of innate immune cells including microglia (MG) and macrophages (MACs). Here we show myeloid cell restricted expression of triggering receptor expressed on myeloid cells 2 (TREM2) across low- and high-grade human gliomas. TREM2 expression did not correlate with immunosuppressive pathways, but rather showed strong positive association with phagocytosis markers such as lysozyme (LYZ) and CD163 in gliomas. In line with these observations in patient tumors, Trem2 -/- mice did not exhibit improved survival compared to wildtype (WT) mice when implanted with mouse glioma cell lines, unlike observations previously seen in peripheral tumor models. Gene expression profiling revealed pathways related to inflammation, adaptive immunity, and autophagy that were significantly downregulated in tumors from Trem2 -/- mice compared to WT tumors. Using ZsGreen-expressing CT-2A orthotopic implants, we found higher tumor antigen engulfment in Trem2 + MACs, MG, and dendritic cells. Our data uncover TREM2 as an important immunomodulator in gliomas and inducing TREM2 mediated phagocytosis can be a potential immunotherapeutic strategy for brain tumors.Key points: TREM2 is not associated with immunosuppressive molecules in GBMTREM2 is associated with phagocytosis in both human and mouse gliomasDeletion of Trem2 in mice does not improve survival in glioma models.
    Importance of the study: Triggering receptor expressed on myeloid cells 2 (TREM2) has been implicated as a major immunoregulator in both neurodegenerative diseases and systemic cancers, yet its functional role in gliomas remains unclear. This study reveals that unlike in other cancers, TREM2 is not associated with immunosuppression in the glioma microenvironment. In fact, TREM2 expression is associated with phagocytosis in both human and mouse gliomas, similar to its role in Alzheimer’s disease. These findings indicate that TREM2 blockade will not be a viable treatment strategy for gliomas. Instead, TREM2 induction may boost the potential of myeloid cells in the tumor microenvironment to engulf cancer cells.
    DOI:  https://doi.org/10.1101/2023.04.05.535792
  2. bioRxiv. 2023 Apr 06. pii: 2023.04.05.535697. [Epub ahead of print]
    TREM2 mediates MHCII-associated CD4 + T cell response against gliomas.
    Jiaying Zheng, Lingxiao Wang, Shunyi Zhao, Wenjing Zhang, Yuzhou Chang, Aastha Dheer, Shan Gao, Shengze Xu, Katayoun Ayasoufi, Rawan Al-Kharboosh, Manling Xie, Aaron J Johnson, Haidong Dong, Alfredo Qui Ones-Hinojosa, Long-Jun Wu.
      Triggering receptor expressed on myeloid cells 2 (TREM2) was recently highlighted as a novel immune suppressive marker in peripheral tumors. The aim of this study was to characterize TREM2 expression in gliomas and investigate its contribution in glioma progression by using Trem2 -/- mouse line. Our results showed that higher TREM2 expression was correlated with poor prognosis in glioma patients. Unexpectedly, TREM2 deficiency did not have a beneficial effect in a pre-clinical model of glioma. The increased TREM2 expression in glioma was likely due to increased myeloid cell infiltration, as evidenced by our single-cell analysis showing that almost all microglia and macrophages in gliomas were TREM2 + . Furthermore, we found that deficiency of TREM2 impaired tumor-myeloid phagocytosis and MHCII presentation, and significantly reduced CD4 + T cells in tumor hemispheres. Our results revealed a previously unrecognized protective role of tumor-myeloid TREM2 in promoting MHCII-associated CD4 + T cell response against gliomas.SUMMARY: Authors found that although higher TREM2 expression is correlated with poor prognosis in glioma patients, its absence has no beneficial effect in a pre-clinical model of glioma. Deficiency of TREM2 impairs myeloid cell phagocytosis of tumor debris, leading to a reduction in MHCII-dependent CD4 + anti-glioma immunity.
    DOI:  https://doi.org/10.1101/2023.04.05.535697
  3. Nat Commun. 2023 Apr 20. 14(1): 2262
    Sema3C signaling is an alternative activator of the canonical WNT pathway in glioblastoma.
    Jing Hao, Xiangzi Han, Haidong Huang, Xingjiang Yu, Jiangkang Fang, Jianjun Zhao, Richard A Prayson, Shideng Bao, Jennifer S Yu.
      The Wnt pathway is frequently dysregulated in many cancers, underscoring it as a therapeutic target. Wnt inhibitors have uniformly failed in clinical trials. Here, we report a mechanism of WNT pathway activation through the Semaphorin 3 C neurodevelopmental program in glioma stem-like cells. Sema3C directs β-catenin nuclear accumulation in a Rac1-dependent process, leading to transactivation of Wnt target genes. Sema3C-driven Wnt signaling occurred despite suppression of Wnt ligand secretion, suggesting that Sema3C drives canonical Wnt signaling independent of Wnt ligand binding. In a mouse model of glioblastoma, combined depletion of Sema3C and β-catenin partner TCF1 extended animal survival more than single target inhibition alone. In human glioblastoma, Sema3C expression and Wnt pathway activation were highly concordant. Since Sema3C is frequently overexpressed in glioblastoma, Sema3C signaling may be a significant mechanism of resistance to upstream Wnt pathway inhibitors. Dual targeting of Sema3C and Wnt pathways may achieve clinically significant Wnt pathway inhibition.
    DOI:  https://doi.org/10.1038/s41467-023-37397-w
  4. Nat Cancer. 2023 Apr 20.
    CD103+ regulatory T cells underlie resistance to radio-immunotherapy and impair CD8+ T cell activation in glioblastoma.
    Luuk van Hooren, Shanna M Handgraaf, Daan J Kloosterman, Elham Karimi, Lotte W H G van Mil, Awa A Gassama, Beatriz Gomez Solsona, Marnix H P de Groot, Dieta Brandsma, Daniela F Quail, Logan A Walsh, Gerben R Borst, Leila Akkari.
      Glioblastomas are aggressive primary brain tumors with an inherent resistance to T cell-centric immunotherapy due to their low mutational burden and immunosuppressive tumor microenvironment. Here we report that fractionated radiotherapy of preclinical glioblastoma models induce a tenfold increase in T cell content. Orthogonally, spatial imaging mass cytometry shows T cell enrichment in human recurrent tumors compared with matched primary glioblastoma. In glioblastoma-bearing mice, α-PD-1 treatment applied at the peak of T cell infiltration post-radiotherapy results in a modest survival benefit compared with concurrent α-PD-1 administration. Following α-PD-1 therapy, CD103+ regulatory T cells (Tregs) with upregulated lipid metabolism accumulate in the tumor microenvironment, and restrain immune checkpoint blockade response by repressing CD8+ T cell activation. Treg targeting elicits tertiary lymphoid structure formation, enhances CD4+ and CD8+ T cell frequency and function and unleashes radio-immunotherapeutic efficacy. These results support the rational design of therapeutic regimens limiting the induction of immunosuppressive feedback pathways in the context of T cell immunotherapy in glioblastoma.
    DOI:  https://doi.org/10.1038/s43018-023-00547-6
  5. Neuro Oncol. 2023 Apr 21. pii: noad079. [Epub ahead of print]
    FAM129A promotes self-renewal and maintains invasive status via stabilizing the Notch intracellular domain in glioma stem cells.
    Guohao Liu, Po Zhang, Sui Chen, Zirong Chen, Yanmei Qiu, Peng Peng, Wenda Huang, Fangling Cheng, Yang Zhang, Huan Li, Qungen Xiao, Feng Mao, Baofeng Wang, Xiaobing Jiang, Feng Wan, Dongsheng Guo, Xingjiang Yu.
      BACKGROUND: Glioma stem cells (GSCs) are a subpopulation of tumor cells with self-renewal and tumorigenic capabilities in glioblastomas (GBMs). Diffuse infiltration of GSCs facilitates tumor progression and frustrates efforts at effective treatment. Further compounding this situation is the currently limited understanding of what drives GSC invasion. Here we comprehensively evaluated the significance of a novel invasion-related protein, Family with Sequence Similarity 129 Member A (FAM129A), in infiltrative GSCs.METHODS: Western blotting, immunohistochemistry, and gene expression analysis were used to quantify FAM129A in glioma specimens and cancer datasets. Overexpression and knockdown of FAM129A in glioma stem cells were used to investigate its effects on tumor growth and invasion. RNA-seq, qRT-PCR, western blotting, and co-precipitation assays were used to investigate FAM129A signaling mechanisms.
    RESULTS: FAM129A is preferentially expressed in invasive frontiers. Targeting FAM129A impairs GSC invasion and self-renewal. Mechanistically, FAM129A acted as a positive regulator of Notch signaling by binding with the Notch1 intracellular domain (NICD1) and preventing its degradation.
    CONCLUSION: FAM129A and NICD1 provide a precise indicator for identifying tumor margins and aiding prognosis. Targeting them may provide a significantly therapeutic strategy for GSCs.
    Keywords:  FAM129A; NICD; Notch pathway; glioma stem cell; tumor invasion
    DOI:  https://doi.org/10.1093/neuonc/noad079
  6. Cancer Res. 2023 Apr 17. OF1-OF17
    Single-Cell Spatial Analysis Identifies Regulators of Brain Tumor-Initiating Cells.
    Reza Mirzaei, Charlotte D'Mello, Marina Liu, Ana Nikolic, Mehul Kumar, Frank Visser, Pinaki Bose, Marco Gallo, V Wee Yong.
      Glioblastomas (GBM) are aggressive brain tumors with extensive intratumoral heterogeneity that contributes to treatment resistance. Spatial characterization of GBMs could provide insights into the role of the brain tumor microenvironment in regulating intratumoral heterogeneity. Here, we performed spatial transcriptomic and single-cell analyses of the mouse and human GBM microenvironment to dissect the impact of distinct anatomical regions of brains on GBM. In a syngeneic GBM mouse model, spatial transcriptomics revealed that numerous extracellular matrix (ECM) molecules, including biglycan, were elevated in areas infiltrated with brain tumor-initiating cells (BTIC). Single-cell RNA sequencing and single-cell assay for transposase-accessible chromatin using sequencing showed that ECM molecules were differentially expressed by GBM cells based on their differentiation and cellular programming phenotypes. Exogeneous biglycan or overexpression of biglycan resulted in a higher proliferation rate of BTICs, which was associated mechanistically with low-density lipoprotein receptor-related protein 6 (LRP6) binding and activation of the Wnt/β-catenin pathway. Biglycan-overexpressing BTICs developed into larger tumors and displayed mesenchymal phenotypes when implanted intracranially in mice. This study points to the spatial heterogeneity of ECM molecules in GBM and suggests that the biglycan-LRP6 axis could be a therapeutic target to curb tumor growth.SIGNIFICANCE: Characterization of the spatial heterogeneity of glioblastoma identifies regulators of brain tumor-initiating cells and tumor growth that could serve as candidates for therapeutic interventions to improve the prognosis of patients.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-22-3004
  7. Nat Commun. 2023 Apr 20. 14(1): 2266
    CAR-neutrophil mediated delivery of tumor-microenvironment responsive nanodrugs for glioblastoma chemo-immunotherapy.
    Yun Chang, Xuechao Cai, Ramizah Syahirah, Yuxing Yao, Yang Xu, Gyuhyung Jin, Vijesh J Bhute, Sandra Torregrosa-Allen, Bennett D Elzey, You-Yeon Won, Qing Deng, Xiaojun Lance Lian, Xiaoguang Wang, Omolola Eniola-Adefeso, Xiaoping Bao.
      Glioblastoma (GBM) is one of the most aggressive and lethal solid tumors in human. While efficacious therapeutics, such as emerging chimeric antigen receptor (CAR)-T cells and chemotherapeutics, have been developed to treat various cancers, their effectiveness in GBM treatment has been hindered largely by the blood-brain barrier and blood-brain-tumor barriers. Human neutrophils effectively cross physiological barriers and display effector immunity against pathogens but the short lifespan and resistance to genome editing of primary neutrophils have limited their broad application in immunotherapy. Here we genetically engineer human pluripotent stem cells with CRISPR/Cas9-mediated gene knock-in to express various anti-GBM CAR constructs with T-specific CD3ζ or neutrophil-specific γ-signaling domains. CAR-neutrophils with the best anti-tumor activity are produced to specifically and noninvasively deliver and release tumor microenvironment-responsive nanodrugs to target GBM without the need to induce additional inflammation at the tumor sites. This combinatory chemo-immunotherapy exhibits superior and specific anti-GBM activities, reduces off-target drug delivery and prolongs lifespan in female tumor-bearing mice. Together, this biomimetic CAR-neutrophil drug delivery system is a safe, potent and versatile platform for treating GBM and possibly other devastating diseases.
    DOI:  https://doi.org/10.1038/s41467-023-37872-4
  8. Nat Rev Clin Oncol. 2023 Apr 21.
    Understanding the activity of antibody-drug conjugates in primary and secondary brain tumours.
    Maximilian J Mair, Rupert Bartsch, Emilie Le Rhun, Anna S Berghoff, Priscilla K Brastianos, Javier Cortes, Hui K Gan, Nancy U Lin, Andrew B Lassman, Patrick Y Wen, Michael Weller, Martin van den Bent, Matthias Preusser.
      Antibody-drug conjugates (ADCs), a class of targeted cancer therapeutics combining monoclonal antibodies with a cytotoxic payload via a chemical linker, have already been approved for the treatment of several cancer types, with extensive clinical development of novel constructs ongoing. Primary and secondary brain tumours are associated with high mortality and morbidity, necessitating novel treatment approaches. Pharmacotherapy of brain tumours can be limited by restricted drug delivery across the blood-brain or blood-tumour barrier, although data from phase II studies of the HER2-targeted ADC trastuzumab deruxtecan indicate clinically relevant intracranial activity in patients with brain metastases from HER2+ breast cancer. However, depatuxizumab mafodotin, an ADC targeting wild-type EGFR and EGFR variant III, did not provide a definitive overall survival benefit in patients with newly diagnosed or recurrent EGFR-amplified glioblastoma in phase II and III trials, despite objective radiological responses in some patients. In this Review, we summarize the available data on the central nervous system activity of ADCs from trials involving patients with primary and secondary brain tumours and discuss their clinical implications. Furthermore, we explore pharmacological determinants of intracranial activity and discuss the optimal design of clinical trials to facilitate development of ADCs for the treatment of gliomas and brain metastases.
    DOI:  https://doi.org/10.1038/s41571-023-00756-z
  9. Neuro Oncol. 2023 Apr 20. pii: noad075. [Epub ahead of print]
    Cerebrospinal fluid: the new frontier for methylome-based diagnostic classification of brain tumors.
    Alexandra M Miller, Matthias A Karajannis.
      
    DOI:  https://doi.org/10.1093/neuonc/noad075
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