bims-malgli Biomed News
on Biology of malignant gliomas
Issue of 2024‒04‒07
fourteen papers selected by
Oltea Sampetrean, Keio University
  1. Tumor associated microglia/macrophages utilize GPNMB to promote tumor growth and alter immune cell infiltration in glioma.
  2. Epigenetic Reprogramming of Autophagy Drives Mutant IDH1 Glioma Progression and Response to Radiation.
  3. Mesenchymal glioma stem cells trigger vasectasia-distinct neovascularization process stimulated by extracellular vesicles carrying EGFR.
  4. Circulating extracellular vesicles as biomarker for diagnosis, prognosis and monitoring in glioblastoma patients.
  5. Glioblastoma: Not Just Another Cancer.
  6. Phosphocreatine promotes epigenetic reprogramming to facilitate glioblastoma growth through stabilizing BRD2.
  7. The oncolytic adenovirus Delta-24-RGD in combination with ONC201 induces a potent antitumor response in pediatric high-grade and diffuse midline glioma models.
  8. Strategies to Improve Drug Delivery Across the Blood-Brain Barrier for Glioblastoma.
  9. ERK signaling promotes resistance to TRK kinase inhibition in NTRK fusion-driven glioma mouse models.
  10. Mutant IDH inhibitors induce lineage differentiation in IDH-mutant oligodendroglioma.
  11. Super-enhancer-driven LIF promotes the mesenchymal transition in glioblastoma by activating ITGB2 signaling feedback in microglia.
  12. The Rigidity Connection: Matrix Stiffness and Its Impact on Cancer Progression.
  13. Shifting the landscape: The role of IDH inhibitors in glioma cell fate.
  14. Stressing the Role of CCL3 in Reversing the Immunosuppressive Microenvironment in Gliomas.
  1. Acta Neuropathol Commun. 2024 Apr 02. 12(1): 50
    Tumor associated microglia/macrophages utilize GPNMB to promote tumor growth and alter immune cell infiltration in glioma.
    Fatih Yalcin, Hannah Haneke, Ibrahim E Efe, Leonard D Kuhrt, Edyta Motta, Bernadette Nickl, Charlotte Flüh, Michael Synowitz, Omar Dzaye, Michael Bader, Helmut Kettenmann.
      Tumor-associated microglia and blood-derived macrophages (TAMs) play a central role in modulating the immune suppressive microenvironment in glioma. Here, we show that GPNMB is predominantly expressed by TAMs in human glioblastoma multiforme and the murine RCAS-PDGFb high grade glioma model. Loss of GPNMB in the in vivo tumor microenvironment results in significantly smaller tumor volumes and generates a pro-inflammatory innate and adaptive immune cell microenvironment. The impact of host-derived GPNMB on tumor growth was confirmed in two distinct murine glioma cell lines in organotypic brain slices from GPNMB-KO and control mice. Using published data bases of human glioma, the elevated levels in TAMs could be confirmed and the GPNMB expression correlated with a poorer survival.
    Keywords:  CD44; Experimental glioma; GPNMB; Glioblastoma; Macrophage; Microglia; Mouse; RCAS
    DOI:  https://doi.org/10.1186/s40478-024-01754-7
  2. bioRxiv. 2024 Mar 13. pii: 2024.03.08.584091. [Epub ahead of print]
    Epigenetic Reprogramming of Autophagy Drives Mutant IDH1 Glioma Progression and Response to Radiation.
    Felipe J Núñez, Kaushik Banerjee, Anzar A Mujeeb, Ava Mauser, Claire E Tronrud, Ziwen Zhu, Ayman Taher, Padma Kadiyala, Stephen V Carney, Maria B Garcia-Fabiani, Andrea Comba, Mahmoud S Alghamri, Brandon L McClellan, Syed M Faisal, Zeribe C Nwosu, Hanna S Hong, Tingting Qin, Maureen A Sartor, Mats Ljungman, Shi-Yuan Cheng, Henry D Appelman, Pedro R Lowenstein, Joerg Lahann, Costas A Lyssiotis, Maria G Castro.
      Mutant isocitrate dehydrogenase 1 (mIDH1; IDH1 R132H ) exhibits a gain of function mutation enabling 2-hydroxyglutarate (2HG) production. 2HG inhibits DNA and histone demethylases, inducing epigenetic reprogramming and corresponding changes to the transcriptome. We previously demonstrated 2HG-mediated epigenetic reprogramming enhances DNA-damage response and confers radioresistance in mIDH1 gliomas harboring p53 and ATRX loss of function mutations. In this study, RNA-seq and ChIP-seq data revealed human and mouse mIDH1 glioma neurospheres have downregulated gene ontologies related to mitochondrial metabolism and upregulated autophagy. Further analysis revealed that the decreased mitochondrial metabolism was paralleled by a decrease in glycolysis, rendering autophagy as a source of energy in mIDH1 glioma cells. Analysis of autophagy pathways showed that mIDH1 glioma cells exhibited increased expression of pULK1-S555 and enhanced LC3 I/II conversion, indicating augmented autophagy activity. This dependence is reflected by increased sensitivity of mIDH1 glioma cells to autophagy inhibition. Blocking autophagy selectively impairs the growth of cultured mIDH1 glioma cells but not wild-type IDH1 (wtIDH1) glioma cells. Targeting autophagy by systemic administration of synthetic protein nanoparticles packaged with siRNA targeting Atg7 (SPNP-siRNA-Atg7) sensitized mIDH1 glioma cells to radiation-induced cell death, resulting in tumor regression, long-term survival, and immunological memory, when used in combination with IR. Our results indicate autophagy as a critical pathway for survival and maintenance of mIDH1 glioma cells, a strategy that has significant potential for future clinical translation.One Sentence Summary: The inhibition of autophagy sensitizes mIDH1 glioma cells to radiation, thus creating a promising therapeutic strategy for mIDH1 glioma patients.
    Graphical abstract: Our genetically engineered mIDH1 mouse glioma model harbors IDH1 R132H in the context of ATRX and TP53 knockdown. The production of 2-HG elicited an epigenetic reprogramming associated with a disruption in mitochondrial activity and an enhancement of autophagy in mIDH1 glioma cells. Autophagy is a mechanism involved in cell homeostasis related with cell survival under energetic stress and DNA damage protection. Autophagy has been associated with radio resistance. The inhibition of autophagy thus radio sensitizes mIDH1 glioma cells and enhances survival of mIDH1 glioma-bearing mice, representing a novel therapeutic target for this glioma subtype with potential applicability in combined clinical strategies.
    DOI:  https://doi.org/10.1101/2024.03.08.584091
  3. Nat Commun. 2024 Apr 03. 15(1): 2865
    Mesenchymal glioma stem cells trigger vasectasia-distinct neovascularization process stimulated by extracellular vesicles carrying EGFR.
    Cristiana Spinelli, Lata Adnani, Brian Meehan, Laura Montermini, Sidong Huang, Minjun Kim, Tamiko Nishimura, Sidney E Croul, Ichiro Nakano, Yasser Riazalhosseini, Janusz Rak.
      Targeting neovascularization in glioblastoma (GBM) is hampered by poor understanding of the underlying mechanisms and unclear linkages to tumour molecular landscapes. Here we report that different molecular subtypes of human glioma stem cells (GSC) trigger distinct endothelial responses involving either angiogenic or circumferential vascular growth (vasectasia). The latter process is selectively triggered by mesenchymal (but not proneural) GSCs and is mediated by a subset of extracellular vesicles (EVs) able to transfer EGFR/EGFRvIII transcript to endothelial cells. Inhibition of the expression and phosphorylation of EGFR in endothelial cells, either pharmacologically (Dacomitinib) or genetically (gene editing), abolishes their EV responses in vitro and disrupts vasectasia in vivo. Therapeutic inhibition of EGFR markedly extends anticancer effects of VEGF blockade in mice, coupled with abrogation of vasectasia and prolonged survival. Thus, vasectasia driven by intercellular transfer of oncogenic EGFR may represent a new therapeutic target in a subset of GBMs.
    DOI:  https://doi.org/10.1038/s41467-024-46597-x
  4. Neuro Oncol. 2024 Apr 03. pii: noae068. [Epub ahead of print]
    Circulating extracellular vesicles as biomarker for diagnosis, prognosis and monitoring in glioblastoma patients.
    Franz L Ricklefs, Kathrin Wollmann, Amanda Salviano-Silva, Richard Drexler, Cecile L Maire, Michael G Kaul, Rudolph Reimer, Ulrich Schüller, Sarina Heinemann, Katharina Kolbe, Tobias Mummert, Markus Glatzel, Sven Peine, Jens Gempt, Manfred Westphal, Lasse Dührsen, Katrin Lamszus.
      BACKGROUND: Extracellular vesicles (EVs) obtained by noninvasive liquid biopsy from patient blood can serve as biomarkers. Here, we investigated the potential of circulating plasma EVs to serve as an indicator in the diagnosis, prognosis and treatment response of glioblastoma patients.METHODS: Plasma samples were collected from glioblastoma patients at multiple timepoints before and after surgery. EV concentrations were measured by nanoparticle tracking analysis and imaging flow cytometry. Tumor burden and edema were quantified by 3D reconstruction. EVs and tumors were further monitored in glioma-bearing mice.
    RESULTS: Glioblastoma patients displayed a 5.5-fold increase in circulating EVs compared to healthy donors (p < 0.0001). Patients with higher EV levels had a significantly shorter overall survival and progression-free survival than patients with lower levels, and the plasma EV concentration was an independent prognostic parameter for overall survival. EV levels correlated with the extent of peritumoral FLAIR hyperintensity but not with the size of the contrast-enhancing tumor, and similar findings were obtained in mice. Postoperatively, EV concentrations decreased rapidly back to normal levels, and the magnitude of the decline was associated with the extent of tumor resection. EV levels remained low during stable disease, but increased again upon tumor recurrence. In some patients, EV resurgence preceded the magnetic resonance imaging (MRI) detectability of tumor relapse.
    CONCLUSIONS: Our findings suggest that leakiness of the blood-brain barrier may primarily be responsible for the high circulating EV concentrations in glioblastoma patients. Elevated EVs reflect tumor presence, and their quantification may thus be valuable in assessing disease activity.
    Keywords:  Glioma; blood; exosome; methylation; tetraspanin
    DOI:  https://doi.org/10.1093/neuonc/noae068
  5. Cancer Discov. 2024 Apr 04. 14(4): 648-652
    Glioblastoma: Not Just Another Cancer.
    Howard A Fine.
      SUMMARY: This commentary urges a paradigm shift in how we approach research and drug development for glioblastoma, reimagining it as an aberrant brain-like organ, distinct from other cancers, to inspire innovative treatment strategies and interdisciplinary collaboration, addressing the minimal progress in extending glioblastoma patient survival despite years of research and investment.
    DOI:  https://doi.org/10.1158/2159-8290.CD-23-1498
  6. Cancer Discov. 2024 Apr 02.
    Phosphocreatine promotes epigenetic reprogramming to facilitate glioblastoma growth through stabilizing BRD2.
    Lishu Chen, Qinghui Qi, Xiaoqing Jiang, Jin Wu, Yuanyuan Li, Zhaodan Liu, Yan Cai, Haowen Ran, Songyang Zhang, Cheng Zhang, Huiran Wu, Shuailiang Cao, Lanjuan Mi, Dake Xiao, Haohao Huang, Shuai Jiang, Jiaqi Wu, Bohan Li, Jiong Xie, Ji Qi, Fangye Li, Panpan Liang, Qiuying Han, Min Wu, Wenchao Zhou, Chenhui Wang, Weina Zhang, Xin Jiang, Kun Zhang, Huiyan Li, Xuemin Zhang, Ailing Li, Tao Zhou, Jianghong Man.
      Glioblastoma (GBM) exhibits profound metabolic plasticity for survival and therapeutic resistance, while the underlying mechanisms remain unclear. Here, we show that GBM stem cells (GSCs) reprogram the epigenetic landscape by producing substantial amounts of phosphocreatine (PCr). This production is attributed to the elevated transcription of brain-type creatine kinase (CKB), mediated by Zinc finger E-box binding homeobox 1 (ZEB1). PCr inhibits the poly-ubiquitination of the chromatin regulator bromodomain containing protein 2 (BRD2) by outcompeting the E3 ubiquitin ligase SPOP for BRD2 binding. Pharmacological disruption of PCr biosynthesis by cyclocreatine leads to BRD2 degradation and a decrease in its targets' transcription, which inhibits chromosome segregation and cell proliferation. Notably, cyclocreatine treatment significantly impedes tumor growth and sensitizes tumors to a BRD2 inhibitor in mouse GBM models without detectable side effects. These findings highlight that high production of PCr is a druggable metabolic feature of GBM and a promising therapeutic target for GBM treatment.
    DOI:  https://doi.org/10.1158/2159-8290.CD-23-1348
  7. Neuro Oncol. 2024 Mar 30. pii: noae066. [Epub ahead of print]
    The oncolytic adenovirus Delta-24-RGD in combination with ONC201 induces a potent antitumor response in pediatric high-grade and diffuse midline glioma models.
    Daniel de la Nava, Iker Ausejo-Mauleon, Virginia Laspidea, Marisol Gonzalez-Huarriz, Andrea Lacalle, Noelia Casares, Marta Zalacain, Lucía Marrodan, Marc García-Moure, Maria C Ochoa, Antonio Carlos Tallon-Cobos, Reyes Hernandez-Osuna, Javier Marco-Sanz, Laasya Dhandapani, Irati Hervás-Corpión, Oren J Becher, Javad Nazarian, Sabine Mueller, Timothy N Phoenix, Jasper van der Lugt, Mikel Hernaez, Elizabeth Guruceaga, Carl Koschmann, Sriram Venneti, Joshua E Allen, Matthew D Dun, Juan Fueyo, Candelaria Gomez-Manzano, Jaime Gallego Perez-Larraya, Ana Patiño-García, Sara Labiano, Marta M Alonso.
      BACKGROUND: Pediatric high-grade gliomas (pHGGs), including diffuse midline gliomas (DMGs), are aggressive pediatric tumors with one of the poorest prognoses. Delta-24-RGD and ONC201 have shown promising efficacy as single agents for these tumors. However, the combination of both agents has not been evaluated.METHODS: The production of functional viruses was assessed by immunoblotting and replication assays. The antitumor effect was evaluated in a panel of human and murine pHGG and DMG cell lines. RNAseq, the seahorse stress test, mitochondrial DNA content, and γH2A.X immunofluorescence were used to perform mechanistic studies. Mouse models of both diseases were used to assess the efficacy of the combination in vivo. The tumor immune microenvironment was evaluated using flow cytometry, RNAseq and multiplexed immunofluorescence staining.
    RESULTS: The Delta-24-RGD/ONC201 combination did not affect the virus replication capability in human pHGG and DMG models in vitro. Cytotoxicity analysis showed that the combination treatment was either synergistic or additive. Mechanistically, the combination treatment increased nuclear DNA damage and maintained the metabolic perturbation and mitochondrial damage caused by each agent alone. Delta-24-RGD/ONC201 cotreatment extended the overall survival of mice implanted with human and murine pHGG and DMG cells, independent of H3 mutation status and location. Finally, combination treatment in murine DMG models revealed a reshaping of the tumor microenvironment to a proinflammatory phenotype.
    CONCLUSIONS: The Delta-24-RGD/ONC201 combination improved the efficacy compared to each agent alone in in vitro and in vivo models by potentiating nuclear DNA damage and in turn improving the antitumor (immune) response to each agent alone.
    Keywords:  DMGs; Delta-24-RGD; ONC201; immunovirotherapy; pHGGs
    DOI:  https://doi.org/10.1093/neuonc/noae066
  8. Curr Neurol Neurosci Rep. 2024 Apr 05.
    Strategies to Improve Drug Delivery Across the Blood-Brain Barrier for Glioblastoma.
    Kazim H Narsinh, Edgar Perez, Alexander F Haddad, Jacob S Young, Luis Savastano, Javier E Villanueva-Meyer, Ethan Winkler, John de Groot.
      PURPOSE OF REVIEW: Glioblastoma remains resistant to most conventional treatments. Despite scientific advances in the past three decades, there has been a dearth of effective new treatments. New approaches to drug delivery and clinical trial design are needed.RECENT FINDINGS: We discuss how the blood-brain barrier and tumor microenvironment pose challenges for development of effective therapies for glioblastoma. Next, we discuss treatments in development that aim to overcome these barriers, including novel drug designs such as nanoparticles and antibody-drug conjugates, novel methods of drug delivery, including convection-enhanced and intra-arterial delivery, and novel methods to enhance drug penetration, such as blood-brain barrier disruption by focused ultrasound and laser interstitial thermal therapy. Lastly, we address future opportunities, positing combination therapy as the best strategy for effective treatment, neoadjuvant and window-of-opportunity approaches to simultaneously enhance therapeutic effectiveness with interrogation of on-treatment biologic endpoints, and adaptive platform and basket trials as imperative for future trial design. New approaches to GBM treatment should account for the blood-brain barrier and immunosuppression by improving drug delivery, combining treatments, and integrating novel clinical trial designs.
    Keywords:  Clinical trials; Convection-enhanced delivery; Drug delivery; Focused ultrasound; GBM; Glioblastoma; Laser interstitial thermal therapy
    DOI:  https://doi.org/10.1007/s11910-024-01338-x
  9. bioRxiv. 2024 Mar 26. pii: 2024.03.13.584849. [Epub ahead of print]
    ERK signaling promotes resistance to TRK kinase inhibition in NTRK fusion-driven glioma mouse models.
    Sebastian Schmid, Zachary R Russell, Alex Shimura Yamashita, Madeline E West, Abigail G Parrish, Julia Walker, Dmytro Rudoy, James Z Yan, David C Quist, Betemariyam N Gessesse, Neriah Alvinez, Patrick J Cimino, Debra K Kumasaka, Ralph E Parchment, Eric C Holland, Frank Szulzewsky.
      Pediatric-type high-grade gliomas frequently harbor gene fusions involving receptor tyrosine kinase genes, including neurotrophic tyrosine kinase receptor (NTRK) fusions. Clinically, these tumors show high initial response rates to tyrosine kinase inhibition but ultimately recur due to the accumulation of additional resistance-conferring mutations. Here, we developed a series of genetically engineered mouse models of treatment-naïve and -experienced NTRK1/2/3 fusion-driven gliomas. Both the TRK kinase domain and the N-terminal fusion partners influenced tumor histology and aggressiveness. Treatment with TRK kinase inhibitors significantly extended survival of NTRK fusion-driven glioma mice in a fusion- and inhibitor-dependent manner, but tumors ultimately recurred due to the presence of treatment-resistant persister cells. Finally, we show that ERK activation promotes resistance to TRK kinase inhibition and identify MEK inhibition as a potential combination therapy. These models will be invaluable tools for preclinical testing of novel inhibitors and to study the cellular responses of NTRK fusion-driven gliomas to therapy.
    DOI:  https://doi.org/10.1101/2024.03.13.584849
  10. Cancer Cell. 2024 Apr 02. pii: S1535-6108(24)00093-X. [Epub ahead of print]
    Mutant IDH inhibitors induce lineage differentiation in IDH-mutant oligodendroglioma.
    Avishay Spitzer, Simon Gritsch, Masashi Nomura, Alexander Jucht, Jerome Fortin, Ramya Raviram, Hannah R Weisman, L Nicolas Gonzalez Castro, Nicholas Druck, Rony Chanoch-Myers, John J Y Lee, Ravindra Mylvaganam, Rachel Lee Servis, Jeremy Man Fung, Christine K Lee, Hiroaki Nagashima, Julie J Miller, Isabel Arrillaga-Romany, David N Louis, Hiroaki Wakimoto, Will Pisano, Patrick Y Wen, Tak W Mak, Marc Sanson, Mehdi Touat, Dan A Landau, Keith L Ligon, Daniel P Cahill, Mario L Suvà, Itay Tirosh.
      A subset of patients with IDH-mutant glioma respond to inhibitors of mutant IDH (IDHi), yet the molecular underpinnings of such responses are not understood. Here, we profiled by single-cell or single-nucleus RNA-sequencing three IDH-mutant oligodendrogliomas from patients who derived clinical benefit from IDHi. Importantly, the tissues were sampled on-drug, four weeks from treatment initiation. We further integrate our findings with analysis of single-cell and bulk transcriptomes from independent cohorts and experimental models. We find that IDHi treatment induces a robust differentiation toward the astrocytic lineage, accompanied by a depletion of stem-like cells and a reduction of cell proliferation. Furthermore, mutations in NOTCH1 are associated with decreased astrocytic differentiation and may limit the response to IDHi. Our study highlights the differentiating potential of IDHi on the cellular hierarchies that drive oligodendrogliomas and suggests a genetic modifier that may improve patient stratification.
    Keywords:  IDH1; differentiation therapy; glioma; ivosidenib; oligodendroglioma; single cell RNA-seq; vorasidenib
    DOI:  https://doi.org/10.1016/j.ccell.2024.03.008
  11. Neuro Oncol. 2024 Mar 30. pii: noae065. [Epub ahead of print]
    Super-enhancer-driven LIF promotes the mesenchymal transition in glioblastoma by activating ITGB2 signaling feedback in microglia.
    Han Xie, Yanyi Jiang, Yufei Xiang, Baoming Wu, Jiajia Zhao, Ruixiang Huang, Mengting Wang, Yunlong Wang, Jun Liu, Dejun Wu, Dasheng Tian, Erbao Bian.
      BACKGROUND: The mesenchymal (MES) subtype of glioblastoma (GBM) is believed to be influenced by both cancer cell-intrinsic alterations and extrinsic cellular interactions, yet the underlying mechanisms remain unexplored.METHODS: Identification of microglial heterogeneity by bioinformatics analysis. Transwell migration, invasion assays, and tumor models were used to determine gene function and the role of small molecule inhibitors. RNA sequencing, chromatin immunoprecipitation, and dual-luciferase reporter assays were performed to explore the underlying regulatory mechanisms.
    RESULTS: We identified the inflammatory microglial subtype of tumor-associated microglia (TAM) and found that its specific gene ITGB2 was highly expressed in TAM of MES GBM tissues. Mechanistically, the activation of ITGB2 in microglia promoted the interaction between the SH2 domain of STAT3 and the cytoplasmic domain of ITGB2, thereby stimulating the JAK1/STAT3/IL-6 signaling feedback to promote the MES transition of GBM cells. Additionally, microglia communicated with GBM cells through the interaction between the receptor ITGB2 on microglia and the ligand ICAM-1 on GBM cells, while an increased secretion of ICAM-1 was induced by the proinflammatory cytokine LIF. Further studies demonstrated that inhibition of CDK7 substantially reduced the recruitment of SNW1 to the super-enhancer of LIF, resulting in transcriptional inhibition of LIF. We identified notoginsenoside R1 as a novel LIF inhibitor that exhibited synergistic effects in combination with temozolomide.
    CONCLUSIONS: Our research reveals that the epigenetic-mediated interaction of GBM cells with TAM drives the MES transition of GBM and provides a novel therapeutic avenue for patients with MES GBM.
    Keywords:  GBM; MES transition; TAM; super-enhancer
    DOI:  https://doi.org/10.1093/neuonc/noae065
  12. Cancer Res. 2024 Apr 01. 84(7): 958-960
    The Rigidity Connection: Matrix Stiffness and Its Impact on Cancer Progression.
    Anna Yui, Madeleine J Oudin.
      The extracellular matrix (ECM) has always been studied in the context of the structural support it provides tissues. However, more recently, it has become clear that ECM proteins do more to regulate biological processes relevant to cancer progression: from activating complex signaling pathways to presenting soluble growth factors. In 2009, Ulrich and colleagues provided evidence that the physical properties of the ECM could also contribute to glioblastoma tumor cell proliferation and invasion using tunable hydrogels, emphasizing a role for tumor rigidity in central nervous system cancer progression. Here, we will discuss the results of this landmark article, as well as highlight other work that has shown the importance of tissue stiffness in glioblastoma and other tumor types in the tumor microenvironment. Finally, we will discuss how this research has led to the development of novel treatments for cancer that target tumor rigidity. See related article by Ulrich and colleagues, Cancer Res 2009;69:4167-74.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-24-0394
  13. Cancer Cell. 2024 Mar 29. pii: S1535-6108(24)00052-7. [Epub ahead of print]
    Shifting the landscape: The role of IDH inhibitors in glioma cell fate.
    Skylar A Giacobetti, Howard A Fine.
      In this issue of Cancer Cell, Spitzer and colleagues demonstrate the role of IDH inhibitors on IDHmutant gliomas in reducing proliferation and enhancing cell differentiation toward an astrocytic-like state, thus altering neurodevelopmental pathways. Despite clinical promise, unresolved questions regarding mechanisms of action and resistance underline the need for further research for treatment optimization.
    DOI:  https://doi.org/10.1016/j.ccell.2024.02.008
  14. Cancer Immunol Res. 2024 Apr 02. OF1
    Stressing the Role of CCL3 in Reversing the Immunosuppressive Microenvironment in Gliomas.
    Xiaoteng Cui, Chunsheng Kang.
      Patients with gliomas often experience mental health problems, such as depression and anxiety, that lead to worsening tumor progression and shortened survival. In this issue, Wang and colleagues report a novel mechanism underlying this, finding that chronic stress reduces secretion of the chemokine CCL3, which leads to an immunosuppressive glioma microenvironment. CCL3 administration enhances the infiltration of antitumor immune cells, providing rationale for a potential new therapeutic approach. See related article by Wang et al.
    DOI:  https://doi.org/10.1158/2326-6066.CIR-24-0254
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