bims-malgli Biomed News
on Biology of malignant gliomas
Issue of 2023‒01‒08
eight papers selected by
Oltea Sampetrean
Keio University
  1. Wnt Signaling Regulates MFSD2A-dependent Drug Delivery through Endothelial Transcytosis in Glioma.
  2. Macrophages and microglia in glioblastoma: heterogeneity, plasticity, and therapy.
  3. Monocyte-neutrophil entanglement in glioblastoma.
  4. The immune landscape of high-grade brain tumor after treatment with immune checkpoint blockade.
  5. Activated T cell therapy targeting glioblastoma cancer stem cells.
  6. Identification of glioblastoma-specific antigens expressed in patient-derived tumor cells as candidate targets for chimeric antigen receptor T cell therapy.
  7. Targeting fatty acid metabolism in glioblastoma.
  8. MATRIX platform to analyze translation machinery remodeling in glioblastoma cells.
  1. Neuro Oncol. 2023 Jan 02. pii: noac288. [Epub ahead of print]
    Wnt Signaling Regulates MFSD2A-dependent Drug Delivery through Endothelial Transcytosis in Glioma.
    Yuan Xie, Liqun He, Yanyu Zhang, Hua Huang, Fan Yang, Min Chao, Haiyan Cao, Jianhao Wang, Yaling Li, Lingxue Zhang, Lele Xin, Bing Xiao, Xinxin Shi, Xue Zhang, Jiefu Tang, Lene Uhrbom, Anna Dimberg, Liang Wang, Lei Zhang.
      BACKGROUND: Systemic delivery of anti-tumor therapeutic agents to brain tumors is thwarted by the blood-brain barrier (BBB), an organotypic specialization of brain endothelial cells (ECs). A failure of pharmacological compounds to cross BBB is one culprit for the dismal prognosis of glioblastoma (GBM) patients. Identification of novel vascular targets to overcome the challenges posed by the BBB in tumors for GBM treatment is urgently needed.METHODS: Temozolomide (TMZ) delivery was investigated in CT2A and PDGFB-driven RCAS/tv-a orthotopic glioma models. Transcriptome analysis was performed on ECs from murine gliomas. Mfsd2a deficient, Cav1 deficient and Mfsd2a EC specific inducible mice were developed to study the underlying molecular mechanisms.
    RESULTS: We demonstrated that inhibiting Wnt signaling by LGK974 could increase TMZ delivery and sensitize glioma to chemotherapy in both murine glioma models. Transcriptome analysis of ECs from murine gliomas revealed that Wnt signaling inhibition enhanced vascular transcytosis as indicated by the upregulation of PLVAP and downregulation of MSFD2A. Mfsd2a deficiency in mice enhances TMZ delivery in tumors, whereas constitutive expression of Mfsd2a in ECs suppresses the enhanced TMZ delivery induced by Wnt pathway inhibition in murine glioma. In addition, Wnt signaling inhibition enhanced caveolin-1 (Cav1)-positive caveolae-mediated transcytosis in tumor ECs. Moreover, Wnt signaling inhibitor or Mfsd2a deficiency fails to enhance TMZ penetration in tumors from Cav1-deficient mice.
    CONCLUSIONS: These results demonstrated that Wnt signaling regulates MFSD2A-dependent TMZ delivery through a caveolae-mediated EC transcytosis pathway. Our findings identify Wnt signaling as a promising therapeutic target to improve drug delivery for GBM treatment.
    Keywords:  Wnt signaling; blood-brain barrier; drug delivery; endothelial cell; glioblastoma
    DOI:  https://doi.org/10.1093/neuonc/noac288
  2. J Clin Invest. 2023 Jan 03. pii: e163446. [Epub ahead of print]133(1):
    Macrophages and microglia in glioblastoma: heterogeneity, plasticity, and therapy.
    Fatima Khan, Lizhi Pang, Madeline Dunterman, Maciej S Lesniak, Amy B Heimberger, Peiwen Chen.
      Glioblastoma (GBM) is the most aggressive tumor in the central nervous system and contains a highly immunosuppressive tumor microenvironment (TME). Tumor-associated macrophages and microglia (TAMs) are a dominant population of immune cells in the GBM TME that contribute to most GBM hallmarks, including immunosuppression. The understanding of TAMs in GBM has been limited by the lack of powerful tools to characterize them. However, recent progress on single-cell technologies offers an opportunity to precisely characterize TAMs at the single-cell level and identify new TAM subpopulations with specific tumor-modulatory functions in GBM. In this Review, we discuss TAM heterogeneity and plasticity in the TME and summarize current TAM-targeted therapeutic potential in GBM. We anticipate that the use of single-cell technologies followed by functional studies will accelerate the development of novel and effective TAM-targeted therapeutics for GBM patients.
    DOI:  https://doi.org/10.1172/JCI163446
  3. J Clin Invest. 2023 Jan 03. pii: e163451. [Epub ahead of print]133(1):
    Monocyte-neutrophil entanglement in glioblastoma.
    Dinorah Friedmann-Morvinski, Dolores Hambardzumyan.
      Glioblastoma (GBM) is the most belligerent and frequent brain tumor in adults. Research over the past two decades has provided increased knowledge of the genomic and molecular landscape of GBM and highlighted the presence of a high degree of inter- and intratumor heterogeneity within the neoplastic compartment. It is now appreciated that GBMs are composed of multiple distinct and impressionable neoplastic and non-neoplastic cell types that form the unique brain tumor microenvironment (TME). Non-neoplastic cells in the TME form reciprocal interactions with neoplastic cells to promote tumor growth and invasion, and together they influence the tumor response to standard-of-care therapies as well as emerging immunotherapies. One of the most prevalent non-neoplastic cell types in the GBM TME are myeloid cells, the most abundant of which are of hematopoietic origin, including monocytes/monocyte-derived macrophages. Less abundant, although still a notable presence, are neutrophils of hematopoietic origin and intrinsic brain-resident microglia. In this Review we focus on neutrophils and monocytes that infiltrate tumors from the blood circulation, their heterogeneity, and their interactions with neoplastic cells and other non-neoplastic cells in the TME. We conclude with an overview of challenges in targeting these cells and discuss avenues for therapeutic exploitation to improve the dismal outcomes of patients with GBM.
    DOI:  https://doi.org/10.1172/JCI163451
  4. Front Immunol. 2022 ;13 1044544
    The immune landscape of high-grade brain tumor after treatment with immune checkpoint blockade.
    Jang Hyun Park, In Kang, Heung Kyu Lee.
      Despite the therapeutic success of immune checkpoint blockade (ICB) therapy against multiple tumors, many patients still do not benefit from ICB. In particular, high-grade brain tumors, such as glioblastoma multiforme (GBM), have a very low response rate to ICB, resulting in several failed clinical trials. This low response rate might be caused by a lack of understanding of the unique characteristics of brain immunity. To overcome this knowledge gap, macroscopic studies of brain immunity are needed. We use single cell RNA sequencing to analyze the immune landscape of the tumor microenvironment (TME) under anti-PD-1 antibody treatment in a murine GBM model. We observe that CD8 T cells show a mixed phenotype overall that includes reinvigoration and re-exhaustion states. Furthermore, we find that CCL5 induced by anti-PD-1 treatment might be related to an increase in the number of anti-inflammatory macrophages in the TME. Therefore, we hypothesize that CCL5-mediated recruitment of anti-inflammatory macrophages may be associated with re-exhaustion of CD8 T cells in the TME. We compare our observations in the murine GBM models with publicly available data from human patients with recurrent GBM. Our study provides critical information for the development of novel immunotherapies to overcome the limitations of anti-PD-1 therapy.
    Keywords:  CCL5 - chemokine ligand 5; CD8 T cell; GBM - Glioblastoma multiforme; PD-1; tumor microenvirenment
    DOI:  https://doi.org/10.3389/fimmu.2022.1044544
  5. Sci Rep. 2023 Jan 05. 13(1): 196
    Activated T cell therapy targeting glioblastoma cancer stem cells.
    Ken Miyaguchi, Hongqiang Wang, Keith L Black, Stephen L Shiao, Rongfu Wang, John S Yu.
      Naïve T cells become effector T cells following stimulation by antigen-loaded dendritic cells (DCs) and sequential cytokine activation. We aimed to develop procedures to efficiently activate T cells with tumor-associated antigens (TAAs) to glioblastoma (GBM) stem cells. To remove antigen presentation outside of the immunosuppressive tumor milieu, three different glioma stem cell (GSC) specific antigen sources to load DCs were compared in their ability to stimulate lymphocytes. An activated T cell (ATC) protocol including cytokine activation and expansion in culture to target GSCs was generated and optimized for a planned phase I clinical trial. We compared three different antigen-loading methods on DCs to effectively activate T cells, which were GBM patient-derived GSC-lysate, acid-eluate of GSCs and synthetic peptides derived from proteins expressed in GSCs. DCs derived from HLA-A2 positive blood sample were loaded with TAAs. Autologous T cells were activated by co-culturing with loaded DCs. Efficiency and cytotoxicity of ATCs were evaluated by targeting TAA-pulsed DCs or T2 cells, GSCs, or autologous PHA-blasts. Characteristics of ATCs were evaluated by Flow Cytometry and ELISpot assay, which showed increased number of ATCs secreting IFN-γ targeting GSCs as compared with non-activated T cells and unloaded target cells. Neither GSC-lysate nor acid-eluate loading showed enhancement in response of ATCs but the synthetic peptide pool showed significantly increased IFN-γ secretion and increased cytotoxicity towards target cells. These results demonstrate that ATCs activated using a TAA synthetic peptide pool efficiently enhance cytotoxicity specifically to target cells including GSC.
    DOI:  https://doi.org/10.1038/s41598-022-27184-w
  6. Neurooncol Adv. 2023 Jan-Dec;5(1):5(1): vdac177
    Identification of glioblastoma-specific antigens expressed in patient-derived tumor cells as candidate targets for chimeric antigen receptor T cell therapy.
    Tomoyoshi Nakagawa, Noriyuki Kijima, Kana Hasegawa, Shunya Ikeda, Moto Yaga, Tansri Wibowo, Tetsuro Tachi, Hideki Kuroda, Ryuichi Hirayama, Yoshiko Okita, Manabu Kinoshita, Naoki Kagawa, Yonehiro Kanemura, Naoki Hosen, Haruhiko Kishima.
      Background: New therapies for glioblastoma (GBM) are urgently needed because the disease prognosis is poor. Chimeric antigen receptor (CAR)-T cell therapy that targets GBM-specific cell surface antigens is a promising therapeutic strategy. However, extensive transcriptome analyses have uncovered few GBM-specific target antigens.Methods: We established a library of monoclonal antibodies (mAbs) against a tumor cell line derived from a patient with GBM. We identified mAbs that reacted with tumor cell lines from patients with GBM but not with nonmalignant human brain cells. We then detected the antigens they recognized using expression cloning. CAR-T cells derived from a candidate mAb were generated and tested in vitro and in vivo.
    Results: We detected 507 mAbs that bound to tumor cell lines from patients with GBM. Among them, E61 and A13 reacted with tumor cell lines from most patients with GBM, but not with nonmalignant human brain cells. We found that B7-H3 was the antigen recognized but E61. CAR-T cells were established using the antigen-recognition domain of E61-secreted cytokines and exerted cytotoxicity in co-culture with tumor cells from patients with GBM.
    Conclusions: Cancer-specific targets for CAR-T cells were identified using a mAb library raised against primary GBM tumor cells from a patient. We identified a GBM-specific mAb and its antigen. More mAbs against various GBM samples and novel target antigens are expected to be identified using this strategy.
    Keywords:  B7-H3; CAR-T cell therapy; expression cloning; glioblastoma (GBM); monoclonal antibody
    DOI:  https://doi.org/10.1093/noajnl/vdac177
  7. J Clin Invest. 2023 Jan 03. pii: e163448. [Epub ahead of print]133(1):
    Targeting fatty acid metabolism in glioblastoma.
    Jason Miska, Navdeep S Chandel.
      Glioblastoma (GBM) is a primary tumor of the brain defined by its uniform lethality and resistance to conventional therapies. There have been considerable efforts to untangle the metabolic underpinnings of this disease to find novel therapeutic avenues for treatment. An emerging focus in this field is fatty acid (FA) metabolism, which is critical for numerous diverse biological processes involved in GBM pathogenesis. These processes can be classified into four broad fates: anabolism, catabolism, regulation of ferroptosis, and the generation of signaling molecules. Each fate provides a unique perspective by which we can inspect GBM biology and gives us a road map to understanding this complicated field. This Review discusses the basic, translational, and clinical insights into each of these fates to provide a contemporary understanding of FA biology in GBM. It is clear, based on the literature, that there are far more questions than answers in the field of FA metabolism in GBM, and substantial efforts should be made to untangle these complex processes in this intractable disease.
    DOI:  https://doi.org/10.1172/JCI163448
  8. STAR Protoc. 2022 Dec 16. pii: S2666-1667(22)00799-7. [Epub ahead of print]3(4): 101919
    MATRIX platform to analyze translation machinery remodeling in glioblastoma cells.
    J J David Ho, Tyler A Cunningham, Jonathan R Krieger, Jonathan H Schatz, Stephen Lee.
      Here, we present a protocol using MATRIX (mass spectrometry analysis of active translation factors using ribosome density fractionation and isotopic labeling experiments) platform to investigate changes of the protein synthesis machinery in U87MG glioblastoma cells in response to the rocaglate silvestrol. This protocol describes steps to perform SILAC (stable isotope labeling by amino acids in cell culture), ribosome density fractionation, protein isolation, and mass spectrometry analysis. This approach can be applied to study any adaptive remodeling of protein synthesis machineries. For complete details on the use and execution of this protocol, please refer to Ho et al. (2021).1.
    Keywords:  Cancer; Mass Spectrometry; Protein Biochemistry; Proteomics
    DOI:  https://doi.org/10.1016/j.xpro.2022.101919
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