bims-malgli 2024-09-08 papers

bims-malgli

Biomed News

on Biology of malignant gliomas

Issue of 2024–09–08
twenty papers selected by
Oltea Sampetrean, Keio University

Microglia in Glioma.
Neurosteroids in Glioma: A Novel Therapeutic Concept.
Metabolomic profile of cerebrospinal fluid from patients with diffuse gliomas.
B cell-based therapy produces antibodies that inhibit glioblastoma growth.
Dysbiosis of the gut microbiota in glioblastoma patients and potential biomarkers for risk assessment.
Microenvironment T-Type calcium channels regulate neuronal and glial processes to promote glioblastoma growth.
The compartment-specific manipulation of the NAD+/NADH ratio affects the metabolome and the function of glioblastoma.
The oncological role of resection in newly diagnosed diffuse adult-type glioma defined by the WHO 2021 classification: a Review by the RANO resect group.
Modeling glioblastoma tumor progression via CRISPR-engineered brain organoids.
Polymer-locking fusogenic liposomes for glioblastoma-targeted siRNA delivery and CRISPR-Cas gene editing.
Glioblastoma mesenchymal subtype enhances antioxidant defence to reduce susceptibility to ferroptosis.
Acid-sensing ion channel 3 is a new potential therapeutic target for the control of glioblastoma cancer stem cells growth.
Durable benefit and slowdown in tumor growth dynamics with erdafitinib in a FGFR3-TACC3 fusion-positive IDH-wild type glioblastoma.
Galectin-9 Mediates the Functions of Microglia in the Hypoxic Brain Tumor Microenvironment.
Epigenetic therapy potentiates transposable element transcription to create tumor-enriched antigens in glioblastoma cells.
Immune landscape of oncohistone-mutant gliomas reveals diverse myeloid populations and tumor-promoting function.
Macrophage migration inhibitory factor as a therapeutic target in neuro-oncology: A review.
GABAergic neuronal lineage development determines clinically actionable targets in diffuse hemispheric glioma, H3G34-mutant.
Protocol to analyze 1D and 2D mass spectrometry data from glioblastoma tissues for cancer diagnosis and immune cell identification.
Therapeutic efficacy of IL-7/CCL19-expressing CAR-T cells in intractable solid tumor models of glioblastoma and pancreatic cancer.

Adv Neurobiol. 2024 ;37 513-527

Microglia in Glioma.

Stefano Garofalo, Giuseppina D'Alessandro, Cristina Limatola.

  Myeloid cells are fundamental constituents of the brain tumor microenvironment. In this chapter, we describe the state-of-the-art knowledge on the role of microglial cells in the cross-talk with the most common and aggressive brain tumor, glioblastoma. We report in vitro and in vivo studies related to glioblastoma patients and glioma models to outline the symbiotic interactions that microglia develop with tumoral cells, highlighting the heterogeneity of microglial functions in shaping the brain tumor microenvironment.

Keywords:  Cold Tumor; Glioblastoma; Glioma-associated microglia/macrophages; Lymphocytes; Tumor Microenvironment

DOI:  https://doi.org/10.1007/978-3-031-55529-9_28
Life (Basel). 2024 Aug 02. pii: 975. [Epub ahead of print]14(8):

Neurosteroids in Glioma: A Novel Therapeutic Concept.

Ava Hogan, Melike Mut.

  Glioma, a diverse group of brain and spinal cord tumors arising from glial cells, is characterized by varying degrees of malignancy, with some types exhibiting highly aggressive behavior, rapid proliferation, and invasive growth patterns, posing significant therapeutic challenges. This review delves into the complex interactions between glioma cells, neurotransmitters, and neurosteroids, emphasizing their potential as therapeutic targets. Key neurotransmitters, like glutamate and gamma-aminobutyric acid (GABA), play crucial roles in glioma growth, invasion, and treatment response. This review examines the involvement of neurosteroids in glioma biology and explores innovative therapeutic strategies targeting these systems. It encompasses the biosynthesis and mechanisms of neurosteroids, interactions between gliomas and neurotransmitters, the spatial distribution of neurosteroid synthesis in gliomas, the role of ion channels, hormonal influences, enzyme modulation, and the neuroimmune system in glioma progression. Additionally, it highlights the potential of neurosteroids to modulate these pathways for therapeutic benefit.

Keywords:  glioblastoma; glioma; neuro-oncology; neurosteroids; surgical intervention; therapeutic targets

DOI:  https://doi.org/10.3390/life14080975
J Neurol. 2024 Sep 03.

Metabolomic profile of cerebrospinal fluid from patients with diffuse gliomas.

Nora Möhn, Harold F Hounchonou, Sandra Nay, Philipp Schwenkenbecher, Lea Grote-Levi, Fadi Al-Tarawni, Majid Esmailezadeh, Sven Schuchardt, Kerstin Schwabe, Herbert Hildebrandt, Hauke Thiesler, Friedrich Feuerhake, Christian Hartmann, Thomas Skripuletz, Joachim K Krauss.

   BACKGROUND: Diffuse gliomas are among the most common brain tumors in adults and are associated with a dismal prognosis, especially in patients with glioblastoma. To date, tumor tissue acquisition is mandatory for conclusive diagnosis and therapeutic decision-making. In this study, we aimed to identify possible diagnostic and prognostic biomarkers in cerebrospinal fluid (CSF) and blood.
METHODS: During glioma surgery at our institution, CSF and blood samples were collected from patients. Subsequently, targeted metabolomics analysis was used to detect and quantify circulating metabolites. The metabolome profiles of glioma patients were compared with those of patients in a control group who had undergone neurosurgery for other entities, such as nonglial tumors or hydrocephalus, and were correlated with established glioma diagnostic molecular markers.
RESULTS: In this study, a total of 30 glioma patients were included, along with a control group of 21 patients without glioma. Serum metabolomic analysis did not detect any significant differences between the groups, whereas CSF-metabolome analysis revealed increased levels of six metabolites in glioma patients. Among these, the most pronounced differences were found for the biogenic amine putrescine (p = 0.00005). p-Cresol sulfate was identified as a potential CSF marker for determining isocitrate dehydrogenase (IDH) status in glioma patients (p = 0.0037).
CONCLUSION: CSF-metabolome profiling, unlike blood profiling, shows promise as a diagnostic tool for glioma patients with the potential to assign molecular subtypes. The next step will involve a larger multicenter study to validate these findings, with the ultimate objective of integrating CSF metabolomics analysis into clinical practice.

Keywords:  Biomarkers; Cerebrospinal fluid; Gliomas; Metabolomic profile; Putrescine

DOI:  https://doi.org/10.1007/s00415-024-12667-9
J Clin Invest. 2024 Aug 29. pii: e177384. [Epub ahead of print]

B cell-based therapy produces antibodies that inhibit glioblastoma growth.

Si Wang, Brandyn A Castro, Joshua L Katz, Victor A Arrieta, Hinda Najem, Gustavo I Vazquez-Cervantes, Hanxiao Wan, Ian E Olson, David Hou, Mark Dapash, Leah K Billingham, Tzu-Yi Chia, Chao Wei, Aida Rashidi, Leonidas C Platanias, Kathleen McCortney, Craig M Horbinski, Roger Stupp, Peng Zhang, Atique U Ahmed, Adam M Sonabend, Amy B Heimberger, Maciej S Lesniak, Cecile Riviere-Cazaux, Terry C Burns, Jason Miska, Mariafausta Fischietti, Catalina Lee-Chang.

  Glioblastoma (GBM) is a highly aggressive and malignant brain tumor with limited therapeutic options and a poor prognosis. Despite current treatments, the invasive nature of GBM often leads to recurrence. A promising alternative strategy is to harness the potential of the immune system against tumor cells. Our previous data showed that the Bvax (B-cell-based vaccine) can induce therapeutic responses in preclinical models of GBM. In this study, we aim to characterize the antigenic reactivity of BVax-derived antibodies and evaluate their therapeutic potential. We performed immunoproteomics and functional assays in murine models and human GBM patient samples. Our investigations revealed that BVax distributes throughout the GBM tumor microenvironment (TME) and then differentiates into antibody-producing plasmablasts. Proteomic analyses indicate that the antibodies produced by BVax display unique reactivity, predominantly targeting factors associated with cell motility and the extracellular matrix. Crucially, these antibodies inhibit critical processes such as GBM cell migration and invasion. These findings provide valuable insights into the therapeutic potential of BVax-derived antibodies for GBM patients, pointing towards a novel direction in GBM immunotherapy.

Keywords:  Brain cancer; Cancer immunotherapy; Extracellular matrix; Immunology; Oncology

DOI:  https://doi.org/10.1172/JCI177384
Microb Pathog. 2024 Aug 29. pii: S0882-4010(24)00355-3. [Epub ahead of print]195 106888

Dysbiosis of the gut microbiota in glioblastoma patients and potential biomarkers for risk assessment.

Haixiao Jiang, Fang Yang, Xiaoli Zhang, Huie Fang, Tao Qiu, Yuping Li, Aijun Peng.

   BACKGROUND: The significant death rate of glioblastoma is well-known around the world. The link between gut microbiota and glioma is becoming more studied. The goal of this study was to look at the relationships between intestinal flora and glioblastoma, and to provide a new perspective for the diagnosis as well as treatment of glioblastoma.
METHODS: Fecal samples from 80 participants with glioblastoma (n = 40) and healthy individuals (n = 40) in this study were collected as well as analyzed utilizing 16S rRNA gene amplicon sequencing in order to characterize the gut microbial community.
RESULTS: Each group has its own microbial community, and the microbial environment of glioblastoma patients had lower richness and evenness. The structure of gut microbiota community in glioblastoma patients showed profound changes, which includes the increase of pathogens in Fusobacteria and Bacteroidetes, and the reduction of probiotic bacteria in Firmicutes, Actinobacteria and Verrucomicrobia. Meanwhile, the significant correlations and clustering of OTUS (operational taxonomic units) in glioblastoma patients were discovered, and a biomarker panel (Fusobacterium, Escherichia/Shigella, Ruminococcus gnavus group, Lachnospira, Akkermansia, Parasutterella) had been used to discriminate the patients with glioblastoma from the healthy subjects (AUC: 0.80). Furthermore, the glioblastoma group exhibited multiple disturbed pathways through KEGG (Kyoto Encyclopedia of Genes and Genomes) analysis, particularly in genetic information processing. Moreover, the prediction of phenotypic characteristics of microbiome proposed that the glioblastoma patients might have more Gram-negative bacteria and opportunistic pathogens than the healthy controls.
CONCLUSIONS: When compared to healthy people, glioblastoma sufferers have a different host-microbe interaction. Furthermore, certain types of intestinal flora could be regarded as biomarkers and drug targets for the diagnosis as well as treatment of glioblastomas.

Keywords:  Biomarker; Glioblastoma; Gut microbiota; Gut-brain axis; Microbiota-gut-immune

DOI:  https://doi.org/10.1016/j.micpath.2024.106888
bioRxiv. 2024 Aug 23. pii: 2024.08.22.609229. [Epub ahead of print]

Microenvironment T-Type calcium channels regulate neuronal and glial processes to promote glioblastoma growth.

Collin J Dube, Ying Zhang, Shekhar Saha, Michelle Lai, Myron Keith Gibert, Miguel Escalante, Kadie Hudson, Doris Wong, Pawel Marcinkiewicz, Ulas Yener, Yunan Sun, Esther Xu, Aditya Sorot, Elizabeth Mulcahy, Benjamin A Kefas, Farina Hanif, Fadilla Guessous, Manoj K Patel, David Schiff, Hui Zong, Benjamin W Purow, Eric Holland, Swapnil K Sonkusare, Harald Sontheimer, Roger Abounader.

Background Glioblastoma (GBM) is the most common primary malignant brain tumor. The aim of this study was to elucidate the role of microenvironment and intrinsic T-type calcium channels (Cav3) in regulating tumor growth and progression. Methods We grafted syngeneic GBM cells into Cav3.2 knockout mice to assess the role of microenvironment T-Type calcium channels on GBM tumor growth. We performed single-cell RNA-seq (scRNA-seq) of tumors from WT and Cav3.2 KO mice to elucidate the regulation of tumors by the microenvironment. We used neurons from WT and Cav3.2 KO mice in co-culture with GBM stem cells (GSC) to assess the effects of Cav3.2 on neuron/GSC synaptic connections and tumor cell growth. Results Cav3.2 KO in the microenvironment led to significant reduction of GBM growth and prolongation of animal survival. scRNA-seq showed that microenvironment Cav3.2 regulates neuronal and glial biological processes. Microenvironment Cav3.2 downregulated numerous genes associated with regulating the OPC cell state in GBM tumors such as SOX10 and Olig2. Neuronal Cav3.2 promoted neuron/GSC synaptic connections and GSC growth. Treatment of GSCs with the Cav3 blocker mibefradil downregulated genes associated with neuronal processes. The Cav3 blocker drug mibefradil synergized with temozolomide (TMZ) and radiation to reduce in vivo tumor growth and prolong animal survival. Conclusions Together these data reveal a role for microenvironment Cav3 in promoting GBM tumor progression through regulating neuronal and glial processes particularly associated with the OPC-cell state. Targeting both intrinsic and microenvironment Cav3 with the inhibitor mibefradil significantly enhanced the anti-GBM effects of TMZ and radiation.

DOI: https://doi.org/10.1101/2024.08.22.609229
Sci Rep. 2024 09 04. 14(1): 20575

The compartment-specific manipulation of the NAD+/NADH ratio affects the metabolome and the function of glioblastoma.

Myunghoon Lee, Jae Hong Yoo, Inseo Kim, Sinbeom Kang, Wonsik Lee, Sungjin Kim, Kyung-Seok Han.

  Glioblastoma multiforme (GBM) is the most aggressive type of cancer in the brain and has an inferior prognosis because of the lack of suitable medicine, largely due to its tremendous invasion. GBM has selfish metabolic pathways to promote migration, invasion, and proliferation compared to normal cells. Among various metabolic pathways, NAD (nicotinamide adenine dinucleotide) is essential in generating ATP and is used as a resource for cancer cells. LbNOX (Lactobacillus brevis NADH oxidase) is an enzyme that can directly manipulate the NAD+/NADH ratio. In this study, we found that an increased NAD+/NADH ratio by LbNOX or mitoLbNOX reduced intracellular glutamate and calcium responses and reduced invasion capacity in GBM. However, the invasion was not affected in GBM by rotenone, an ETC (Electron Transport Chain) complex I inhibitor, or nicotinamide riboside, a NAD+ precursor, suggesting that the crucial factor is the NAD+/NADH ratio rather than the absolute quantity of ATP or NAD+ for the invasion of GBM. To develop a more accurate and effective GBM treatment, our findings highlight the importance of developing a new medicine that targets the regulation of the NAD+/NADH ratio, given the current lack of effective treatment options for this brain cancer.

Keywords:   LbNOX; Glioblastoma; Glutamate; Invasion; NAD+/NADH

DOI:  https://doi.org/10.1038/s41598-024-71462-8
Lancet Oncol. 2024 Sep;pii: S1470-2045(24)00130-X. [Epub ahead of print]25(9): e404-e419

The oncological role of resection in newly diagnosed diffuse adult-type glioma defined by the WHO 2021 classification: a Review by the RANO resect group.

Philipp Karschnia, Jasper K W Gerritsen, Nico Teske, Daniel P Cahill, Asgeir S Jakola, Martin van den Bent, Michael Weller, Oliver Schnell, Einar O Vik-Mo, Niklas Thon, Arnaud J P E Vincent, Michelle M Kim, Guido Reifenberger, Susan M Chang, Shawn L Hervey-Jumper, Mitchel S Berger, Joerg-Christian Tonn.

Glioma resection is associated with prolonged survival, but neuro-oncological trials have frequently refrained from quantifying the extent of resection. The Response Assessment in Neuro-Oncology (RANO) resect group is an international, multidisciplinary group that aims to standardise research practice by delineating the oncological role of surgery in diffuse adult-type gliomas as defined per WHO 2021 classification. Favourable survival effects of more extensive resection unfold over months to decades depending on the molecular tumour profile. In tumours with a more aggressive natural history, supramaximal resection might correlate with additional survival benefit. Weighing the expected survival benefits of resection as dictated by molecular tumour profiles against clinical factors, including the introduction of neurological deficits, we propose an algorithm to estimate the oncological effects of surgery for newly diagnosed gliomas. The algorithm serves to select patients who might benefit most from extensive resection and to emphasise the relevance of quantifying the extent of resection in clinical trials.

DOI: https://doi.org/10.1016/S1470-2045(24)00130-X
bioRxiv. 2024 Aug 03. pii: 2024.08.02.606387. [Epub ahead of print]

Modeling glioblastoma tumor progression via CRISPR-engineered brain organoids.

Matthew Ishahak, Rowland H Han, Devi Annamalai, Timothy Woodiwiss, Colin McCornack, Ryan T Cleary, Patrick A DeSouza, Xuan Qu, Sonika Dahiya, Albert H Kim, Jeffrey R Millman.

Glioblastoma (GBM) is an aggressive form of brain cancer that is highly resistant to therapy due to significant intra-tumoral heterogeneity. The lack of robust in vitro models to study early tumor progression has hindered the development of effective therapies. Here, we develop engineered GBM organoids (eGBOs) harboring GBM subtype-specific oncogenic mutations to investigate the underlying transcriptional regulation of tumor progression. Single-cell and spatial transcriptomic analyses revealed that these mutations disrupt normal neurodevelopment gene regulatory networks resulting in changes in cellular composition and spatial organization. Upon xenotransplantation into immunodeficient mice, eGBOs form tumors that recapitulate the transcriptional and spatial landscape of human GBM samples. Integrative single-cell trajectory analysis of both eGBO-derived tumor cells and patient GBM samples revealed the dynamic gene expression changes in developmental cell states underlying tumor progression. This analysis of eGBOs provides an important validation of engineered cancer organoid models and demonstrates their utility as a model of GBM tumorigenesis for future preclinical development of therapeutics.

DOI: https://doi.org/10.1101/2024.08.02.606387
Nat Nanotechnol. 2024 Aug 29.

Polymer-locking fusogenic liposomes for glioblastoma-targeted siRNA delivery and CRISPR-Cas gene editing.

Yu Zhao, Jie Qin, Daohan Yu, Yuxiang Liu, Dan Song, Kaifu Tian, Hao Chen, Qile Ye, Xinyu Wang, Tianye Xu, Hanwen Xuan, Nan Sun, Wenbin Ma, Junzhe Zhong, Penggang Sun, Yu Song, Jingze Hu, Yunlei Zhao, Xintong Hou, Xiangqi Meng, Chuanlu Jiang, Jinquan Cai.

In patients with glioblastoma (GBM), upregulated midkine (MDK) limits the survival benefits conferred by temozolomide (TMZ). RNA interference (RNAi) and CRISPR-Cas9 gene editing technology are attractive approaches for regulating MDK expression. However, delivering these biologics to GBM tissue is challenging. Here we demonstrate a polymer-locking fusogenic liposome (Plofsome) that can be transported across the blood-brain barrier (BBB) and deliver short interfering RNA or CRISPR-Cas9 ribonucleoprotein complexes into the cytoplasm of GBM cells. Plofsome is designed by integrating a 'lock' into the fusogenic liposome using a traceless reactive oxygen species (ROS)-cleavable linker so that fusion occurs only after crossing the BBB and entering the GBM tissue with high ROS levels. Our results showed that MDK suppression by Plofsomes significantly reduced TMZ resistance and inhibited GBM growth in orthotopic brain tumour models. Importantly, Plofsomes are effective only at tumour sites and not in normal tissues, which improves the safety of combined RNAi and CRISPR-Cas9 therapeutics.

DOI: https://doi.org/10.1038/s41565-024-01769-0
Sci Rep. 2024 Sep 05. 14(1): 20770

Glioblastoma mesenchymal subtype enhances antioxidant defence to reduce susceptibility to ferroptosis.

Simona D'Aprile, Simona Denaro, Alessandro Lavoro, Saverio Candido, Sebastiano Giallongo, Filippo Torrisi, Lucia Salvatorelli, Giacomo Lazzarino, Angela Maria Amorini, Giuseppe Lazzarino, Gaetano Magro, Daniele Tibullo, Massimo Libra, Cesarina Giallongo, Nunzio Vicario, Rosalba Parenti.

  Glioblastoma (GBM) represents an aggressive brain tumor, characterized by intra- and inter-tumoral heterogeneity and therapy resistance, leading to unfavourable prognosis. An increasing number of studies pays attention on the regulation of ferroptosis, an iron-dependent cell death, as a strategy to reverse drug resistance in cancer. However, the debate on whether this strategy may have important implications for the treatment of GBM is still ongoing. In the present study, we used ferric ammonium citrate and erastin to evaluate ferroptosis induction effects on two human GBM cell lines, U-251 MG, with proneural characteristics, and T98-G, with a mesenchymal profile. The response to ferroptosis induction was markedly different between cell lines, indeed T98-G cells showed an enhanced antioxidant defence, with increased glutathione levels, as compared to U-251 MG cells. Moreover, using bioinformatic approaches and analysing publicly available datasets from patients' biopsies, we found that GBM with a mesenchymal phenotype showed an up-regulation of several genes involved in antioxidant mechanisms as compared to proneural subtype. Thus, our results suggest that GBM subtypes differently respond to ferroptosis induction, emphasizing the significance of further molecular studies on GBM to better discriminate between various tumor subtypes and progressively move towards personalized therapy.

Keywords:  Erastin; Ferroptosis; Glioblastoma; Iron overload; Mesenchymal subtype; Proneural subtype

DOI:  https://doi.org/10.1038/s41598-024-72024-8
Sci Rep. 2024 09 03. 14(1): 20421

Acid-sensing ion channel 3 is a new potential therapeutic target for the control of glioblastoma cancer stem cells growth.

Andrea Balboni, Camilla D'Angelo, Nicoletta Collura, Simone Brusco, Claudia Di Berardino, Altea Targa, Beatrice Massoti, Eloise Mastrangelo, Mario Milani, Pierfausto Seneci, Vania Broccoli, Luca Muzio, Rossella Galli, Andrea Menegon.

Glioblastoma (GBM) is the most common malignant primary brain cancer that, despite recent advances in the understanding of its pathogenesis, remains incurable. GBM contains a subpopulation of cells with stem cell-like properties called cancer stem cells (CSCs). Several studies have demonstrated that CSCs are resistant to conventional chemotherapy and radiation thus representing important targets for novel anti-cancer therapies. Proton sensing receptors expressed by CSCs could represent important factors involved in the adaptation of tumours to the extracellular environment. Accordingly, the expression of acid-sensing ion channels (ASICs), proton-gated sodium channels mainly expressed in the neurons of peripheral (PNS) and central nervous system (CNS), has been demonstrated in several tumours and linked to an increase in cell migration and proliferation. In this paper we report that the ASIC3 isoform, usually absent in the CNS and present in the PNS, is enriched in human GBM CSCs while poorly expressed in the healthy human brain. We propose here a novel therapeutic strategy based on the pharmacological activation of ASIC3, which induces a significant GBM CSCs damage while being non-toxic for neurons. This approach might offer a promising and appealing new translational pathway for the treatment of glioblastoma.

DOI: https://doi.org/10.1038/s41598-024-71623-9
Neurooncol Adv. 2024 Jan-Dec;6(1):6(1): vdae139

Durable benefit and slowdown in tumor growth dynamics with erdafitinib in a FGFR3-TACC3 fusion-positive IDH-wild type glioblastoma.

Santiago Cabezas-Camarero, Rebeca Pérez-Alfayate, Carmen Polidura, María Natividad Gómez-Ruiz, Lidia Gil-Martínez, Isabel Casado-Fariñas, Jorge Bartolomé, Pedro Pérez-Segura.

  FGFR3-TACC3 fusion-positive IDH-wild-type (IDH-WT) glioblastoma (GB) is a rare GB subtype occurring in approximately 3% of cases. It is clinical behavior and molecular profile is different from those of fusion-negative IDH-WT GBs. Evidence on the role of FGFR inhibitors in FGFR-altered gliomas is limited. We present the case of a patient with a FGFR3-TACC3 fusion-positive IDH-WT GB that at its second recurrence was treated with the FGFR inhibitor erdafitinib through a compassionate use program. Although no objective response was achieved, an overt deceleration in tumor growth was evidenced and the patient remained on treatment for 5.5 months.

Keywords:  FGFR3-TACC3 fusion; erdafitinib; glioblastoma

DOI:  https://doi.org/10.1093/noajnl/vdae139
Cancer Res. 2024 Aug 29.

Galectin-9 Mediates the Functions of Microglia in the Hypoxic Brain Tumor Microenvironment.

Chanju Lee, Dahee Yu, Hyung-Seok Kim, Ki Sun Kim, Chi Young Chang, Hee Jung Yoon, Su Bin Won, Dae Yeon Kim, Eun Ah Goh, Yong Sun Lee, Jong Bae Park, Sang Soo Kim, Eun Jung Park.

Galectin-9 is a multifaceted regulator of various pathophysiological processes that exerts positive or negative effects in a context-dependent manner. Here, we elucidated the distinctive functional properties of galectin-9 on myeloid cells within the brain tumor microenvironment. Galectin-9-expressing cells were abundant at the hypoxic tumor edge in the tumor-bearing ipsilateral hemisphere compared to the contralateral hemisphere in an intracranial mouse brain tumor model. Galectin-9 was highly expressed in microglia and macrophages in tumor-infiltrating cells. In primary glia, both the expression and secretion of galectin-9 were influenced by tumors. Analysis of a human glioblastoma bulk RNA-sequencing dataset and a single-cell RNA-sequencing dataset from a murine glioma model revealed a correlation between galectin-9 expression and glial cell activation. Notably, the galectin-9high microglial subset was functionally distinct from the galectin-9neg/low subset in the brain tumor microenvironment. Galectin-9high microglia exhibited properties of inflammatory activation and higher rates of cell death, whereas galectin-9neg/low microglia displayed a superior phagocytic ability against brain tumor cells. Blockade of galectin-9 suppressed tumor growth and altered the activity of glial and T cells in a mouse glioma model. Additionally, glial galectin-9 expression was regulated by Hif-2α in the hypoxic brain tumor microenvironment. Myeloid-specific Hif-2α deficiency led to attenuated tumor progression. Together, these findings reveal that galectin-9 on myeloid cells is an immunoregulator and putative therapeutic target in brain tumors.

DOI: https://doi.org/10.1158/0008-5472.CAN-23-3878
Nat Genet. 2024 Sep 02.

Epigenetic therapy potentiates transposable element transcription to create tumor-enriched antigens in glioblastoma cells.

H Josh Jang, Nakul M Shah, Ju Heon Maeng, Yonghao Liang, Noah L Basri, Jiaxin Ge, Xuan Qu, Tatenda Mahlokozera, Shin-Cheng Tzeng, Russell B Williams, Michael J Moore, Devi Annamalai, Justin Y Chen, Hyung Joo Lee, Patrick A DeSouza, Daofeng Li, Xiaoyun Xing, Albert H Kim, Ting Wang.

Inhibiting epigenetic modulators can transcriptionally reactivate transposable elements (TEs). These TE transcripts often generate unique peptides that can serve as immunogenic antigens for immunotherapy. Here, we ask whether TEs activated by epigenetic therapy could appreciably increase the antigen repertoire in glioblastoma, an aggressive brain cancer with low mutation and neoantigen burden. We treated patient-derived primary glioblastoma stem cell lines, an astrocyte cell line and primary fibroblast cell lines with epigenetic drugs, and identified treatment-induced, TE-derived transcripts that are preferentially expressed in cancer cells. We verified that these transcripts could produce human leukocyte antigen class I-presented antigens using liquid chromatography with tandem mass spectrometry pulldown experiments. Importantly, many TEs were also transcribed, even in proliferating nontumor cell lines, after epigenetic therapy, which suggests that targeted strategies like CRISPR-mediated activation could minimize potential side effects of activating unwanted genomic regions. The results highlight both the need for caution and the promise of future translational efforts in harnessing treatment-induced TE-derived antigens for targeted immunotherapy.

DOI: https://doi.org/10.1038/s41588-024-01880-x
Nat Commun. 2024 Sep 05. 15(1): 7769

Immune landscape of oncohistone-mutant gliomas reveals diverse myeloid populations and tumor-promoting function.

Augusto Faria Andrade, Alva Annett, Elham Karimi, Danai Georgia Topouza, Morteza Rezanejad, Yitong Liu, Michael McNicholas, Eduardo G Gonzalez Santiago, Dhana Llivichuzhca-Loja, Arne Gehlhaar, Selin Jessa, Antonella De Cola, Bhavyaa Chandarana, Caterina Russo, Damien Faury, Geoffroy Danieau, Evan Puligandla, Yuhong Wei, Michele Zeinieh, Qing Wu, Steven Hebert, Nikoleta Juretic, Emily M Nakada, Brian Krug, Valerie Larouche, Alexander G Weil, Roy W R Dudley, Jason Karamchandani, Sameer Agnihotri, Daniela F Quail, Benjamin Ellezam, Liza Konnikova, Logan A Walsh, Manav Pathania, Claudia L Kleinman, Nada Jabado.

Histone H3-mutant gliomas are deadly brain tumors characterized by a dysregulated epigenome and stalled differentiation. In contrast to the extensive datasets available on tumor cells, limited information exists on their tumor microenvironment (TME), particularly the immune infiltrate. Here, we characterize the immune TME of H3.3K27M and G34R/V-mutant gliomas, and multiple H3.3K27M mouse models, using transcriptomic, proteomic and spatial single-cell approaches. Resolution of immune lineages indicates high infiltration of H3-mutant gliomas with diverse myeloid populations, high-level expression of immune checkpoint markers, and scarce lymphoid cells, findings uniformly reproduced in all H3.3K27M mouse models tested. We show these myeloid populations communicate with H3-mutant cells, mediating immunosuppression and sustaining tumor formation and maintenance. Dual inhibition of myeloid cells and immune checkpoint pathways show significant therapeutic benefits in pre-clinical syngeneic mouse models. Our findings provide a valuable characterization of the TME of oncohistone-mutant gliomas, and insight into the means for modulating the myeloid infiltrate for the benefit of patients.

DOI: https://doi.org/10.1038/s41467-024-52096-w
Neurooncol Adv. 2024 Jan-Dec;6(1):6(1): vdae142

Macrophage migration inhibitory factor as a therapeutic target in neuro-oncology: A review.

Jakub Jarmula, Juyeun Lee, Adam Lauko, Prajwal Rajappa, Matthew M Grabowski, Andrew Dhawan, Peiwen Chen, Richard Bucala, Michael A Vogelbaum, Justin D Lathia.

  Primary central nervous system (CNS) tumors affect tens of thousands of patients each year, and there is a significant need for new treatments. Macrophage migration inhibitory factor (MIF) is a cytokine implicated in multiple tumorigenic processes such as cell proliferation, vascularization, and immune evasion and is therefore a promising therapeutic target in primary CNS tumors. There are several MIF-directed treatments available, including small-molecule inhibitors, peptide drugs, and monoclonal antibodies. However, only a small number of these drugs have been tested in preclinical models of primary CNS tumors, and even fewer have been studied in patients. Moreover, the brain has unique therapeutic requirements that further make effective targeting challenging. In this review, we summarize the latest functions of MIF in primary CNS tumor initiation and progression. We also discuss advances in MIF therapeutic development and ongoing preclinical studies and clinical trials. Finally, we discuss potential future MIF therapies and the strategies required for successful clinical translation.

Keywords:  glioblastoma; macrophage migration inhibitory factor; tumor microenvironment

DOI:  https://doi.org/10.1093/noajnl/vdae142
Cancer Cell. 2024 Aug 27. pii: S1535-6108(24)00305-2. [Epub ahead of print]

GABAergic neuronal lineage development determines clinically actionable targets in diffuse hemispheric glioma, H3G34-mutant.

Ilon Liu, Gustavo Alencastro Veiga Cruzeiro, Lynn Bjerke, Rebecca F Rogers, Yura Grabovska, Alexander Beck, Alan Mackay, Tara Barron, Olivia A Hack, Michael A Quezada, Valeria Molinari, McKenzie L Shaw, Marta Perez-Somarriba, Sara Temelso, Florence Raynaud, Ruth Ruddle, Eshini Panditharatna, Bernhard Englinger, Hafsa M Mire, Li Jiang, Andrezza Nascimento, Jenna LaBelle, Rebecca Haase, Jacob Rozowsky, Sina Neyazi, Alicia-Christina Baumgartner, Sophia Castellani, Samantha E Hoffman, Amy Cameron, Murry Morrow, Quang-De Nguyen, Giulia Pericoli, Sibylle Madlener, Lisa Mayr, Christian Dorfer, Rene Geyeregger, Christopher Rota, Gerda Ricken, Keith L Ligon, Sanda Alexandrescu, Rodrigo T Cartaxo, Benison Lau, Santhosh Uphadhyaya, Carl Koschmann, Emelie Braun, Miri Danan-Gotthold, Lijuan Hu, Kimberly Siletti, Erik Sundström, Rebecca Hodge, Ed Lein, Sameer Agnihotri, David D Eisenstat, Simon Stapleton, Andrew King, Cristina Bleil, Angela Mastronuzzi, Kristina A Cole, Angela J Waanders, Angel Montero Carcaboso, Ulrich Schüller, Darren Hargrave, Maria Vinci, Fernando Carceller, Christine Haberler, Irene Slavc, Sten Linnarsson, Johannes Gojo, Michelle Monje, Chris Jones, Mariella G Filbin.

Diffuse hemispheric gliomas, H3G34R/V-mutant (DHG-H3G34), are lethal brain tumors lacking targeted therapies. They originate from interneuronal precursors; however, leveraging this origin for therapeutic insights remains unexplored. Here, we delineate a cellular hierarchy along the interneuron lineage development continuum, revealing that DHG-H3G34 mirror spatial patterns of progenitor streams surrounding interneuron nests, as seen during human brain development. Integrating these findings with genome-wide CRISPR-Cas9 screens identifies genes upregulated in interneuron lineage progenitors as major dependencies. Among these, CDK6 emerges as a targetable vulnerability: DHG-H3G34 tumor cells show enhanced sensitivity to CDK4/6 inhibitors and a CDK6-specific degrader, promoting a shift toward more mature interneuron-like states, reducing tumor growth, and prolonging xenograft survival. Notably, a patient with progressive DHG-H3G34 treated with a CDK4/6 inhibitor achieved 17 months of stable disease. This study underscores interneuronal progenitor-like states, organized in characteristic niches, as a distinct vulnerability in DHG-H3G34, highlighting CDK6 as a promising clinically actionable target.

DOI: https://doi.org/10.1016/j.ccell.2024.08.006
STAR Protoc. 2024 Sep 04. pii: S2666-1667(24)00450-7. [Epub ahead of print]5(3): 103285

Protocol to analyze 1D and 2D mass spectrometry data from glioblastoma tissues for cancer diagnosis and immune cell identification.

Yanis Zirem, Léa Ledoux, Michel Salzet, Isabelle Fournier.

  In context of cancer diagnosis-based mass spectrometry (MS), the classification model created is crucial. Moreover, exploration of immune cell infiltration in tissues can offer insights within the tumor microenvironment. Here, we present a protocol to analyze 1D and 2D MS data from glioblastoma tissues for cancer diagnosis and immune cells identification. We describe steps for training the most optimal model and cross-validating it, for discovering robust biomarkers and obtaining their corresponding boxplots as well as creating an immunoscore based on MS-imaging data. For complete details on the use and execution of this protocol, please refer to Zirem et al.1.

Keywords:  Cancer; Computer sciences; Immunology; Mass Spectrometry

DOI:  https://doi.org/10.1016/j.xpro.2024.103285
Cancer Res Commun. 2024 Sep 06.

Therapeutic efficacy of IL-7/CCL19-expressing CAR-T cells in intractable solid tumor models of glioblastoma and pancreatic cancer.

Keisuke Ohta, Yukimi Sakoda, Keishi Adachi, Taro Shinozaki, Masao Nakajima, Hiroyuki Yasuda, Hiroaki Nagano, Koji Tamada.

Cancer immunotherapy using immune checkpoint inhibitors and its combination with other anti-cancer therapies have emerged as a new standard of care, due to the encouraging therapeutic effects in various solid cancers. Nonetheless, glioblastoma and pancreatic cancer remain resistant to immunotherapy and represent intractable cancers with the poorest prognosis. We investigated therapeutic effects of next-generation CAR-T cells producing IL-7 and CCL19 (7×19 CAR-T) in these intractable cancers. Cytotoxic activities and therapeutic effects of 7×19 CAR-T were evaluated in vitro and in vivo, in a model using epidermal growth factor receptor variant III (EGFRvIII)-positive glioblastoma and anti-EGFRvIII CAR-T generated from healthy donor PBMC, or a model using human epidermal growth factor receptor 2 (HER2)-positive pancreatic cancer organoid and anti-HER2 CAR-T generated from the same patient's PBMC. Anti-EGFRvIII 7×19 CAR-T exhibited cytotoxic activity specific to EGFRvIII-positive tumor, induced complete rejection of glioblastoma with massive T cell infiltration and tumor cell death in the tumor tissues, and consequently prolonged mouse survival. Anti-HER2 7×19 CAR-T demonstrated a potent cytotoxic activity against autologous HER2-positive pancreatic cancer organoid and induced complete rejection of autologous tumor along with prolonged mouse survival. Our results suggest that 7×19 CAR-T could become a therapeutic option for glioblastoma and pancreatic cancer. To the best of our knowledge, this study is the first to demonstrate the therapeutic efficacy of next-generation CAR-T in an autologous model using patient-derived tumor organoid and CAR-T generated from the same patient's PBMC, in which unwanted allogeneic immune responses are fully excluded.

DOI: https://doi.org/10.1158/2767-9764.CRC-24-0226