Artículos de revistas: "Glioma, microenvironment, tumor associated macrophages"

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Andersen, Johannes K., Hrvoje Miletic y Jubayer A. Hossain. "Tumor-Associated Macrophages in Gliomas—Basic Insights and Treatment Opportunities". Cancers 14, n.º 5 (4 de marzo de 2022): 1319. http://dx.doi.org/10.3390/cancers14051319.

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Glioma refers to a group of primary brain tumors which includes glioblastoma (GBM), astrocytoma and oligodendroglioma as major entities. Among these, GBM is the most frequent and most malignant one. The highly infiltrative nature of gliomas, and their intrinsic intra- and intertumoral heterogeneity, pose challenges towards developing effective treatments. The glioma microenvironment, in addition, is also thought to play a critical role during tumor development and treatment course. Unlike most other solid tumors, the glioma microenvironment is dominated by macrophages and microglia—collectively known as tumor-associated macrophages (TAMs). TAMs, like their homeostatic counterparts, are plastic in nature and can polarize to either pro-inflammatory or immunosuppressive states. Many lines of evidence suggest that immunosuppressive TAMs dominate the glioma microenvironment, which fosters tumor development, contributes to tumor aggressiveness and recurrence and, very importantly, impedes the therapeutic effect of various treatment regimens. However, through the development of new therapeutic strategies, TAMs can potentially be shifted towards a proinflammatory state which is of great therapeutic interest. In this review, we will discuss various aspects of TAMs in the context of glioma. The focus will be on the basic biology of TAMs in the central nervous system (CNS), potential biomarkers, critical evaluation of model systems for studying TAMs and finally, special attention will be given to the potential targeted therapeutic options that involve the TAM compartment in gliomas.

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Tamai, Sho, Toshiya Ichinose, Taishi Tsutsui, Shingo Tanaka, Farida Garaeva, Hemragul Sabit y Mitsutoshi Nakada. "Tumor Microenvironment in Glioma Invasion". Brain Sciences 12, n.º 4 (15 de abril de 2022): 505. http://dx.doi.org/10.3390/brainsci12040505.

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A major malignant trait of gliomas is their remarkable infiltration capacity. When glioma develops, the tumor cells have already reached the distant part. Therefore, complete removal of the glioma is impossible. Recently, research on the involvement of the tumor microenvironment in glioma invasion has advanced. Local hypoxia triggers cell migration as an environmental factor. The transcription factor hypoxia-inducible factor (HIF) -1α, produced in tumor cells under hypoxia, promotes the transcription of various invasion related molecules. The extracellular matrix surrounding tumors is degraded by proteases secreted by tumor cells and simultaneously replaced by an extracellular matrix that promotes infiltration. Astrocytes and microglia become tumor-associated astrocytes and glioma-associated macrophages/microglia, respectively, in relation to tumor cells. These cells also promote glioma invasion. Interactions between glioma cells actively promote infiltration of each other. Surgery, chemotherapy, and radiation therapy transform the microenvironment, allowing glioma cells to invade. These findings indicate that the tumor microenvironment may be a target for glioma invasion. On the other hand, because the living body actively promotes tumor infiltration in response to the tumor, it is necessary to reconsider whether the invasion itself is friend or foe to the brain.

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Kennedy, Benjamin C., Christopher R. Showers, David E. Anderson, Lisa Anderson, Peter Canoll, Jeffrey N. Bruce y Richard C. E. Anderson. "Tumor-Associated Macrophages in Glioma: Friend or Foe?" Journal of Oncology 2013 (2013): 1–11. http://dx.doi.org/10.1155/2013/486912.

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Tumor-associated macrophages (TAMs) contribute substantially to the tumor mass of gliomas and have been shown to play a major role in the creation of a tumor microenvironment that promotes tumor progression. Shortcomings of attempts at antiglioma immunotherapy may result from a failure to adequately address these effects. Emerging evidence supports an independent categorization of glioma TAMs as alternatively activated M2-type macrophages, in contrast to classically activated proinflammatory M1-type macrophages. These M2-type macrophages exert glioma-supportive effects through reduced anti-tumor functions, increased expression of immunosuppressive mediators, and nonimmune tumor promotion through expression of trophic and invasion-facilitating substances. Much of our work has demonstrated these features of glioma TAMs, and together with the supporting literature will be reviewed here. Additionally, the dynamics of glioma cell-TAM interaction over the course of tumor development remain poorly understood; our efforts to elucidate glioma cell-TAM dynamics are summarized. Finally, the molecular pathways which underlie M2-type TAM polarization and gene expression similarly require further investigation, and may present the most potent targets for immunotherapeutic intervention. Highlighting recent evidence implicating the transcription factor STAT3 in immunosuppressive tumorigenic glioma TAMs, we advocate for gene array-based approaches to identify yet unappreciated expression regulators and effector molecules important to M2-type glioma TAMs polarization and function within the glioma tumor microenvironment.

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Rao, Rohit, Rong Han, Sean Ogurek, Lai Man Wu, Liguo Zhang, Jian Hu, Matthew Garrett, Tim Phoenix, Stephen N. Waggoner y Qing Richard Lu. "TAMI-31. GLIOBLASTOMA GENETIC DRIVERS DICTATE THE FUNCTION OF TUMOR-ASSOCIATED MACROPHAGES/MICROGLIA AND RESPONSES TO CSF1R INHIBITION". Neuro-Oncology 23, Supplement_6 (2 de noviembre de 2021): vi204. http://dx.doi.org/10.1093/neuonc/noab196.815.

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Abstract Tumor-associated macrophages/microglia (TAMs) are prominent microenvironment components in human glioblastoma (GBM) that are potential targets for anti-tumor therapy. However, TAM depletion by CSF1R inhibition showed mixed results in clinical trials. We hypothesized that GBM subtype-specific tumor microenvironment convey distinct sensitivities to TAM targeting. We generated syngeneic PDGFB-driven and RAS-driven GBM models that resemble proneural-like and mesenchymal-like gliomas, and determined the effect of TAM targeting by CSF1R inhibitor PLX3397 on glioma growth and progression. We also investigated the co-targeting of TAMs and angiogenesis on PLX3397-resistant RAS-driven GBM. Using single-cell transcriptomic profiling, we further explored differences in tumor microenvironment compositions and functions between the proneural-like and mesenchymal-like glioma models. We found that the growth of PDGFB-driven tumors was markedly inhibited by PLX3397. In contrast, depletion of TAMs at the early phase accelerated RAS-driven tumor growth and had no effects on other proneural and mesenchymal human GBM models. In addition, PLX3397-resistant RAS-driven tumors did not respond to PI3K signaling inhibition. Single-cell transcriptomic profiling revealed that PDGFB-driven gliomas induced expansion and activation of pro-tumor microglia, whereas mesenchymal RAS-driven gliomas elicited TAMs enriched in pro-inflammatory and angiogenic signaling. Co-targeting of TAMs and angiogenesis decreased cell proliferation and tumor mass in RAS-driven gliomas. Our work identifies functionally distinct TAM subpopulations in the growth of different glioma subtypes. Notably, we uncover a potential responsiveness of resistant mesenchymal-like gliomas to combined anti-angiogenic therapy and CSF1R inhibition. These data highlight the importance of microenvironment landscape characterization to optimally stratify glioma patients for TAM-targeted therapy.

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Wang, Qiang-Wei, Li-Hua Sun, Ying Zhang, Zheng Wang, Zheng Zhao, Zhi-Liang Wang, Kuan-Yu Wang et al. "MET overexpression contributes to STAT4-PD-L1 signaling activation associated with tumor-associated, macrophages-mediated immunosuppression in primary glioblastomas". Journal for ImmunoTherapy of Cancer 9, n.º 10 (octubre de 2021): e002451. http://dx.doi.org/10.1136/jitc-2021-002451.

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BackgroundDysregulated receptor tyrosine kinases, such as the mesenchymal-epidermal transition factor (MET), have pivotal role in gliomas. MET and its interaction with the tumor microenvironment have been previously implicated in secondary gliomas. However, the contribution of MET gene to tumor cells’ ability to escape immunosurveillance checkpoints in primary gliomas, especially in glioblastoma (GBM), which is a WHO grade 4 glioma with the worst overall survival, is still poorly understood.MethodsWe investigated the relationship between MET expression and glioma microenvironment by using multiomics data and aimed to understand the potential implications of MET in clinical practice through survival analysis. RNA expression data from a total of 1243 primary glioma samples (WHO grades 2–4) were assembled, incorporating The Cancer Genome Atlas, Chinese Glioma Genome Atlas, and GSE16011 data sets.ResultsPearson’s correlation test from the three data sets indicated that MET showed a robust correlation with programmed death-ligand 1 (PD-L1) and STAT pathways. Western blot analysis revealed that in GBM cell lines (N33 and LN229), PD-L1 and phosphorylated STAT4 were upregulated by MET activation treatment with hepatocyte growth factor and were downregulated on MET suppression by PLB-1001. Tumor tissue microarray analysis indicated a positive correlation between MET and PD-L1 and macrophage-associated markers. Chromatin immunoprecipitation-PCR assay showed enrichment of STAT4 in the PD-L1 DNA. Transwell co-culture and chemotaxis assays revealed that knockdown of MET in GBM cells inhibited macrophage chemotaxis. Moreover, we performed CIBERSORTx and single-cell RNA sequencing data analysis which revealed an elevated number of macrophages in glioma samples with MET overexpression. Kaplan-Meier survival analysis indicated that activation of the MET/STAT4/PD-L1 pathway and upregulation of macrophages were associated with shorter survival time in patients with primary GBM.ConclusionsThese data indicated that the MET-STAT4-PD-L1 axis and tumor-associated macrophages might enforce glioma immune evasion and were associated with poor prognosis in GBM samples, suggesting potential clinical strategies for targeted therapy combined with immunotherapy in patients with primary GBM.

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Peng, Yichen, Feng Chen, Shenglan Li, Xiu Liu, Can Wang, Chunna Yu y Wenbin Li. "Tumor‐associated macrophages as treatment targets in glioma". Brain Science Advances 6, n.º 4 (diciembre de 2020): 306–23. http://dx.doi.org/10.26599/bsa.2020.9050015.

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Gliomas, the most common primary tumors in the central nervous system (CNS), can be categorized into 4 grades according to the World Health Organization. The most malignant glioma type is grade Ⅳ, also named glioblastoma multiforme (GBM). However, the standard treatment of concurrent temozolomide (TMZ) chemotherapy and radiotherapy after maximum resection does not improve overall survival in patients with GBM. Targeting components of the CNS microenvironment represents a new strategy for improving the efficacy of glioma treatment. Most recent studies focused on T cells. However, there is a growing body of evidence that tumor‐associated macrophages (TAMs) play an important role in tumor progression and can be regulated by a wide array of cytokines or chemokines. New TAM‐associated immunotherapies may improve clinical outcomes by blocking tumor progression and prolonging survival. However, understanding the exact roles and possible mechanisms of TAMs in the tumor environment is necessary for developing this promising therapeutic target and identifying potential diagnostic markers for improved prognosis. This review summarizes the possible interactions between TAMs and glioma progression and discusses the potential therapeutic directions for TAM‐associated immunotherapies.

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Jang, Bum-Sup y In Ah Kim. "Relationship between Macrophage and Radiosensitivity in Human Primary and Recurrent Glioblastoma: In Silico Analysis with Publicly Available Datasets". Biomedicines 10, n.º 2 (27 de enero de 2022): 292. http://dx.doi.org/10.3390/biomedicines10020292.

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The glioblastoma microenvironment predominantly contains tumor-associated macrophages that support tumor growth and invasion. We investigated the relationship between tumor radiosensitivity and infiltrating M1/M2 macrophage profiles in public datasets of primary and recurrent glioblastoma. We estimated the radiosensitivity index (RSI) score based on gene expression rankings. Macrophages were profiled using the deconvolution algorithm CIBERSORTx. Samples from The Cancer Genome Atlas (TCGA), Chinese Glioma Genome Atlas (CGGA), the Ivy Glioblastoma Atlas Project dataset, a single-cell RNA sequencing dataset (GSE84465), Glioma Longitudinal Analysis Consortium (GLASS), and an immunotherapy trial dataset (GSE121810) were included. RSI-high radioresistant tumors were associated with worse overall survival in TCGA and CGGA than RSI-low tumors. M1/M2 macrophage ratios and RSI scores were inversely associated, indicating that radioresistant glioblastoma tumor microenvironments contain more M2 than M1 macrophages. In the single-cell RNA sequencing dataset, the mean RSI of neoplastic cells was positively correlated with high M2 macrophages proportions. A favorable response to programmed cell death protein 1 (PD-1) therapy was observed in recurrent glioblastomas with high M1/M2 macrophage ratios and low RSI scores. In patients with recurrent glioblastoma, fewer M2 macrophages and low RSI scores were associated with improved overall survival. High M2 macrophage proportions may be involved in radioresistant glioblastoma.

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Kim, In Ah y Bum Sup Jang. "TMIC-52. RELATIONSHIP BETWEEN MACROPHAGE AND RADIOSENSITIVITY IN HUMAN PRIMARY AND RECURRENT GLIOBLASTOMA: IN SILICO ANALYSIS WITH PUBLICLY AVAILABLE DATASETS". Neuro-Oncology 24, Supplement_7 (1 de noviembre de 2022): vii283. http://dx.doi.org/10.1093/neuonc/noac209.1096.

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Abstract The glioblastoma microenvironment predominantly contains tumor-associated macrophages that support tumor growth and invasion. We investigated the relationship between tumor radiosensitivity and infiltrating M1/M2 macrophage profiles in public datasets of primary and recurrent glioblastoma. We estimated the radiosensitivity index (RSI) score based on gene expression rankings. Macrophages were profiled using the deconvolution algorithm CIBERSORTx. Samples from The Cancer Genome Atlas (TCGA), Chinese Glioma Genome Atlas (CGGA), the Ivy Glioblastoma Atlas Project dataset, a single-cell RNA sequencing dataset (GSE84465), Glioma Longitudinal Analysis Consortium (GLASS), and an immunotherapy trial dataset (GSE121810) were included. RSI-high radioresistant tumors were associated with worse overall survival in TCGA and CGGA than RSI-low tumors. M1/M2 macrophage ratios and RSI scores were inversely associated, indicating that radioresistant glioblastoma tumor microenvironments contain more M2 than M1 macrophages. In the single-cell RNA sequencing dataset, the mean RSI of neoplastic cells was positively correlated with high M2 macrophages proportions. A favorable response to programmed cell death protein 1 (PD-1) therapy was observed in recurrent glioblastomas with high M1/M2 macrophage ratios and low RSI scores. In patients with recurrent glioblastoma, fewer M2 macrophages and low RSI scores were associated with improved overall survival. High M2 macrophage proportions may be involved in radioresistant glioblastoma.

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Richard, Seidu A. "The Pivotal Immunoregulatory Functions of Microglia and Macrophages in Glioma Pathogenesis and Therapy". Journal of Oncology 2022 (4 de abril de 2022): 1–19. http://dx.doi.org/10.1155/2022/8903482.

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Gliomas are mixed solid tumors composed of both neoplastic and nonneoplastic cells. In glioma microenvironment, the most common nonneoplastic and infiltrating cells are macrophages and microglia. Microglia are the exact phagocytes of the central nervous system, whereas macrophages are myeloid immune cells that are depicted with ardent phagocytosis. Microglia are heterogeneously located in almost all nonoverlapping sections of the brain as well as the spinal cord, while macrophages are derived from circulating monocytes. Microglia and macrophages utilize a variety of receptors for the detection of molecules, particles, and cells that they engulf. Both microglia and peripheral macrophages interact directly with vessels both in the periphery of and within the tumor. In glioma milieu, normal human astrocytes, glioma cells, and microglia all exhibited the ability of phagocytosing glioma cells and precisely apoptotic tumor cells. Also, microglia and macrophages are robustly triggered by the glioma via the expression of chemoattractants such as monocyte chemoattractant protein, stromal-derived factor-1, and macrophage-colony stimulating factor. Glioma-associated microglia and/or macrophages positively correlated with glioma invasiveness, immunosuppression, and patients’ poor outcome, making these cells a suitable target for immunotherapeutic schemes.

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Wei, Jun, Konrad Gabrusiewicz y Amy Heimberger. "The Controversial Role of Microglia in Malignant Gliomas". Clinical and Developmental Immunology 2013 (2013): 1–12. http://dx.doi.org/10.1155/2013/285246.

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Malignant gliomas contain stroma and a variety of immune cells including abundant activated microglia/macrophages. Mounting evidence indicates that the glioma microenvironment converts the glioma-associated microglia/macrophages (GAMs) into glioma-supportive, immunosuppressive cells; however, GAMs can retain intrinsic anti-tumor properties. Here, we review and discuss this duality and the potential therapeutic strategies that may inhibit their glioma-supportive and propagating functions.

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Zhou, Jiayi, Xiaojuan Pei, Yingui Yang, Zhu Wang, Weijie Gao, Ran Ye, Xiantong Zhang et al. "Orphan nuclear receptor TLX promotes immunosuppression via its transcriptional activation of PD-L1 in glioma". Journal for ImmunoTherapy of Cancer 9, n.º 4 (abril de 2021): e001937. http://dx.doi.org/10.1136/jitc-2020-001937.

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BackgroundHigh-grade gliomas are rapidly progressing tumors of the central nervous system, and are associated with poor prognosis and highly immunosuppressive microenvironments. Meanwhile, a better understanding of PD-L1, a major prognostic biomarker for checkpoint immune therapy, regulation may provide insights for developing novel immunotherapeutic strategies for treating gliomas. In the present study, we elucidate the functional significance of the orphan nuclear receptor TLX in human glioma, and its functional role in immune suppression through regulation of PD-L1/PD-1 axis.MethodsTLX and PD-L1 expression patterns, and their association with clinicopathological parameters and immune phenotypes of glioma were analysed using CIBERSORT algorithm and single-sample gene-set enrichment analysis from The Cancer Genome Atlas (n=695) and Chinese Glioma Genome Atlas (n=1018) databases. Protein expression and cellular localization of TLX, PD-L1, and PD-1, as well as the prevalence of cytotoxic tumor-infiltrating lymphocytes (TILs), and tumor-associated macrophages (TAMs), in the glioma immune microenvironment were analyzed via tissue microarray by immunohistochemistry and multiplex immunofluorescence. Glioma allografts and xenografts with TLX manipulation (knockdown/knockout or reverse agonist) were inoculated subcutaneously, or orthotopically into the brains of immunodeficient and immunocompetent mice to assess tumor growth by imaging, and the immune microenvironment by flow cytometry. PD-L1 transcriptional regulation by TLX was analyzed by chromatin immunoprecipitation and luciferase reporter assays.ResultsTLX and PD-L1 expression was positively associated with macrophage-mediated immunosuppressive phenotypes in gliomas. TLX showed significant upregulation and positive correlation with PD-L1. Meanwhile, suppression of TLX significantly inhibited in vivo growth of glioma allografts and xenografts (p<0.05), rescued the antitumoral immune response, significantly decreased the PD-L1+, and glioma-associated macrophage population, and increased cytotoxic lymphocyte infiltration (p<0.05). Mechanistically, TLX binds directly to CD274 (PD-L1) gene promoter and activates CD274 transcription.ConclusionsTLX contributes to glioma malignancy and immunosuppression through transcriptional activation of PD-L1 ligands that bind to PD-1 expressed on both TILs and TAMs. Thus, targeting the druggable TLX may have potential therapeutic significance in glioma immune therapy.

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Cheng, Tong, Manyu Xu, Hui Zhang, Bing Lu, Xiaojing Zhang, Ziheng Wang y Jianfei Huang. "KLHDC8A Expression in Association with Macrophage Infiltration and Oxidative Stress Predicts Unfavorable Prognosis for Glioma". Oxidative Medicine and Cellular Longevity 2022 (19 de septiembre de 2022): 1–14. http://dx.doi.org/10.1155/2022/2694377.

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Background. The tumor immune microenvironment (TME) is associated with cancer progression and immune escape. Although KLHDC8A has been reported in glioma in vitro, the expression and clinical significance of this gene in clinical samples are unknown. Methods. The Cancer Genome Atlas and Chinese Glioma Genome Atlas databases were used to evaluate the mRNA expression level of KLHDC8A and its significance in the glioma TME. Tissue microarray-based multiple immunohistochemical staining was conducted to determine KLHDC8A protein levels and characterize the immune signature of tumor-infiltrating immune cells in gliomas. Results. Tumor cells and tumor-associated macrophages expressed KLHDC8A. The expression of KLHDC8A was higher in glioma tissues than in normal brain tissues and was associated with patient clinical characteristics. Gliomas exhibited a high abundance of macrophages, neutrophils, regulatory T cells, and the immune checkpoint PD-L1, as well as high KLHDC8A expression. Cox regression analysis showed that KLHDC8A+CD68+ macrophages and KLHDC8A predicted unfavorable survival in patients with glioma. Finally, protein-protein interaction network analysis showed that the KLHDC8A expression was associated with hypoxia and oxidative stress. Conclusions. KLHDC8A is a potential marker for the clinical diagnosis of glioma. The immune characteristics of macrophages play a crucial role in predicting patients with glioma, providing a new avenue for targeted glioma therapy.

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Comba, Andrea, Syed M. Faisal, Maria Luisa Varela, Anna Argento, Patrick Dunn, Clifford Abel, Todd Hollon et al. "TMIC-62. INHIBITION OF TUMOR-ASSOCIATED COL1A1 MATRIX ARRESTS GLIOMA MESENCHYMAL TRANSFORMATION AND REPROGRAMS THE TUMOR MICROENVIRONMENT". Neuro-Oncology 24, Supplement_7 (1 de noviembre de 2022): vii285. http://dx.doi.org/10.1093/neuonc/noac209.1106.

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Abstract Tumor mesenchymal transformation (MT) is a hallmark of high-grade gliomas. The mesenchymal state is associated with specific changes related to cell adhesion, migration, and the extracellular matrix. Collagen 1a1 (COL1A1) is a main component of the extracellular matrix in gliomas, and its expression correlates inversely with patient survival. However, the cellular and molecular mechanisms of the tumor-associated COL1A1 matrix in gliomas remains elusive. Our study integrates histopathological features, spatially resolved transcriptomics, cellular dynamics and microenvironment alterations associated with MT in high-grade gliomas. Using deep learning analysis of mouse and human glioma histological samples we identified that the density of areas of MT, named oncostreams, correlates with tumor aggressiveness. Spatial transcriptomics analysis, using laser capture microdissection, identified a signature enriched in extracellular matrix related proteins, in which COL1A1 appeared as a key determinant of mesenchymal organization. Correspondingly, human and mouse high-grade gliomas showed prominent alignment of collagen fibers along these mesenchymal fascicles and higher COL1A1 expression compared to low-grade gliomas. Moreover, RNA fluorescent multiplex assays identified at single cell level that different cells within glioma tumors contribute to COL1A1 expression, including neoplastic cells and perivascular non-neoplastic cells such as ACTA2+, CYR61+ and FAP+. Inhibition of COL1A1 using genetically engineered mouse models decreased areas of mesenchymal transformation and increased survival. COL1A1 downregulation impaired tumor cell proliferation and remodeled the tumor microenvironment by reducing CD68+ macrophages/microglia cells, CD31+ endothelial cells, ACTA2+, CYR61+ and FAP+ perivascular cells, and increased GFAP+ astrocytes infiltration withing the tumor mass. Further studies, using ex-vivo glioma explants demonstrated that CO1A1 downregulation decreased collective invasion of the normal brain, supporting its importance in tumor progression. We propose that COL1A1 expression is a valuable marker for diagnosis, and COL1A1 depletion within glioma tumors is a promising direct or complementary therapeutic approach to reprogram mesenchymal transformation, and halt tumor growth.

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Codrici, Elena, Ana-Maria Enciu, Ionela-Daniela Popescu, Simona Mihai y Cristiana Tanase. "Glioma Stem Cells and Their Microenvironments: Providers of Challenging Therapeutic Targets". Stem Cells International 2016 (2016): 1–20. http://dx.doi.org/10.1155/2016/5728438.

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Malignant gliomas are aggressive brain tumors with limited therapeutic options, possibly because of highly tumorigenic subpopulations of glioma stem cells. These cells require specific microenvironments to maintain their “stemness,” described as perivascular and hypoxic niches. Each of those niches induces particular signatures in glioma stem cells (e.g., activation of Notch signaling, secretion of VEGF, bFGF, SDF1 for the vascular niche, activation of HIF2α, and metabolic reprogramming for hypoxic niche). Recently, accumulated knowledge on tumor-associated macrophages, possibly delineating a third niche, has underlined the role of immune cells in glioma progression,viaspecific chemoattractant factors and cytokines, such as macrophage-colony stimulation factor (M-CSF). The local or myeloid origin of this new component of glioma stem cells niche is yet to be determined. Such niches are being increasingly recognized as key regulators involved in multiple stages of disease progression, therapy resistance, immune-escaping, and distant metastasis, thereby substantially impacting the future development of frontline interventions in clinical oncology. This review focuses on the microenvironment impact on the glioma stem cell biology, emphasizing GSCs cross talk with hypoxic, perivascular, and immune niches and their potential use as targeted therapy.

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Codrici, Elena, Ionela-Daniela Popescu, Cristiana Tanase y Ana-Maria Enciu. "Friends with Benefits: Chemokines, Glioblastoma-Associated Microglia/Macrophages, and Tumor Microenvironment". International Journal of Molecular Sciences 23, n.º 5 (24 de febrero de 2022): 2509. http://dx.doi.org/10.3390/ijms23052509.

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Glioma is the most common primary intracranial tumor and has the greatest prevalence of all brain tumors. Treatment resistance and tumor recurrence in GBM are mostly explained by considerable alterations within the tumor microenvironment, as well as extraordinary cellular and molecular heterogeneity. Soluble factors, extracellular matrix components, tissue-resident cell types, resident or newly recruited immune cells together make up the GBM microenvironment. Regardless of many immune cells, a profound state of tumor immunosuppression is supported and developed, posing a considerable hurdle to cancer cells’ immune-mediated destruction. Several studies have suggested that various GBM subtypes present different modifications in their microenvironment, although the importance of the microenvironment in treatment response has yet to be determined. Understanding the microenvironment and how it changes after therapies is critical because it can influence the remaining invasive GSCs and lead to recurrence. This review article sheds light on the various components of the GBM microenvironment and their roles in tumoral development, as well as immune-related biological processes that support the interconnection/interrelationship between different cell types. Also, we summarize the current understanding of the modulation of soluble factors and highlight the dysregulated inflammatory chemokine/specific receptors cascades/networks and their significance in tumorigenesis, cancer-related inflammation, and metastasis.

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Zheng, Yuqi y Manuel B. Graeber. "Microglia and Brain Macrophages as Drivers of Glioma Progression". International Journal of Molecular Sciences 23, n.º 24 (9 de diciembre de 2022): 15612. http://dx.doi.org/10.3390/ijms232415612.

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Evidence is accumulating that the tumour microenvironment (TME) has a key role in the progression of gliomas. Non-neoplastic cells in addition to the tumour cells are therefore finding increasing attention. Microglia and other glioma-associated macrophages are at the centre of this interest especially in the context of therapeutic considerations. New ideas have emerged regarding the role of microglia and, more recently, blood-derived brain macrophages in glioblastoma (GBM) progression. We are now beginning to understand the mechanisms that allow malignant glioma cells to weaken microglia and brain macrophage defence mechanisms. Surface molecules and cytokines have a prominent role in microglia/macrophage-glioma cell interactions, and we discuss them in detail. The involvement of exosomes and microRNAs forms another focus of this review. In addition, certain microglia and glioma cell pathways deserve special attention. These “synergistic” (we suggest calling them “Janus”) pathways are active in both glioma cells and microglia/macrophages where they act in concert supporting malignant glioma progression. Examples include CCN4 (WISP1)/Integrin α6β1/Akt and CHI3L1/PI3K/Akt/mTOR. They represent attractive therapeutic targets.

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Menna, Grazia, Pier Paolo Mattogno, Carlo Maria Donzelli, Lucia Lisi, Alessandro Olivi y Giuseppe Maria Della Pepa. "Glioma-Associated Microglia Characterization in the Glioblastoma Microenvironment through A ‘Seed-and Soil’ Approach: A Systematic Review". Brain Sciences 12, n.º 6 (31 de mayo de 2022): 718. http://dx.doi.org/10.3390/brainsci12060718.

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Ever since the discovery of tumor-associated immune cells, there has been growing interest in the understanding of the mechanisms underlying the crosstalk between these cells and tumor cells. A “seed and soil” approach has been recently introduced to describe the glioblastoma (GBM) landscape: tumor microenvironments act as fertile “soil” and interact with the “seed” (glial and stem cells compartment). In the following article, we provide a systematic review of the current evidence pertaining to the characterization of glioma-associated macrophages and microglia (GAMs) and microglia and macrophage cells in the glioma tumor microenvironment (TME). Methods: An online literature search was launched on PubMed Medline and Scopus using the following research string: “((Glioma associated macrophages OR GAM OR Microglia) AND (glioblastoma tumor microenvironment OR TME))”. The last search for articles pertinent to the topic was conducted in February 2022. Results: The search of the literature yielded a total of 349 results. A total of 235 studies were found to be relevant to our research question and were assessed for eligibility. Upon a full-text review, 58 articles were included in the review. The reviewed papers were further divided into three categories based on their focus: (1) Microglia maintenance of immunological homeostasis and protection against autoimmunity; (2) Microglia crosstalk with dedifferentiated and stem-like glioblastoma cells; (3) Microglia migratory behavior and its activation pattern. Conclusions: Aggressive growth, inevitable recurrence, and scarce response to immunotherapies are driving the necessity to focus on the GBM TME from a different perspective to possibly disentangle its role as a fertile ‘soil’ for tumor progression and identify within it feasible therapeutic targets. Against this background, our systematic review confirmed microglia to play a paramount role in promoting GBM progression and relapse after treatments. The correct and extensive understanding of microglia–glioma crosstalk could help in understanding the physiopathology of this complex disease, possibly opening scenarios for improvement of treatments.

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Chen, Peiwen, Ronald DePinho y Wang Alan. "TMIC-07. SYMBIOTIC MACROPHAGE-GLIOMA CELL INTERACTIONS REVEAL SYNTHETIC LETHALITY IN PTEN NULL GLIOMA". Neuro-Oncology 21, Supplement_6 (noviembre de 2019): vi248. http://dx.doi.org/10.1093/neuonc/noz175.1041.

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Abstract Heterotypic interactions across diverse cell types of the tumor microenvironment (TME) can enable tumor progression and offer points for potential therapeutic intervention. Employing Glioblastoma Multiforme (GBM) as a model system, we sought to (i) understand the nature of specific oncogenic signals in glioma cells that affects immune cells, and (ii) identify immune cell factors which may support glioma growth and survival. Combined profiling and functional studies of glioma cells established that PTEN deficiency, a signature GBM alteration, specifically tracks with an immune profile dominated by tumor-associated macrophages (TAMs, a key type of immune cells in GBM which can constitute up to half of the tumor mass) via upregulation of lysyl oxidase (LOX). Mechanistically, the PTEN-SRC/AKT axis regulates YAP1, which directly upregulates LOX expression and secretion in glioma cells via binding to the LOX promoter. The secreted LOX from glioma cells functions as a potent macrophage chemoattractant to promote macrophage recruitment via activation of the beta1 integrin-PYK2 pathway in macrophages. Consequently, these infiltrating macrophages secrete SPP1 (secreted phosphoprotein 1) which sustains glioma cell survival and stimulates angiogenesis. In human and mouse PTEN-null GBM models, but not PTEN-intact GBM models, LOX inhibition markedly inhibits tumor growth and extends the survival of tumor-bearing mice by decreasing macrophage infiltration, impairing SPP1 expression and attenuating angiogenesis. In silico analysis of human GBM shows that increased YAP1-LOX and b1 integrin-SPP1 signaling positively correlates with higher macrophage density and lower overall survival. Together, the symbiotic glioma (PTEN-YAP1-LOX) and macrophage (beta1 integrin-PYK2-SPP1) interactions provide novel therapeutic targets for this intractable disease.

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Perelroizen, R., B. Philosof, N. Budick-Harmelin, T. Chernobylsky, K. Rotem, A. Ron, D. Shimon et al. "P12.15.B Astrocyte immunometabolic regulation of the glioblastoma microenvironment drives tumor pathogenicity". Neuro-Oncology 24, Supplement_2 (1 de septiembre de 2022): ii80. http://dx.doi.org/10.1093/neuonc/noac174.280.

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Abstract Background Malignant brain tumors are the cause of a disproportionate level of morbidity and mortality among cancer patients, an unfortunate statistic that has remained constant for decades. Despite considerable advances in the molecular characterization of these tumors, targeting the cancer cells has yet to produce significant advances in treatment. An alternative strategy is to target cells in the glioblastoma microenvironment, such as tumor associated astrocytes. Astrocytes control multiple processes in health and disease, ranging from maintaining the brain's metabolic homeostasis, to modulating neuroinflammation. However, their role in glioblastoma pathogenicity is not well understood. Material and Methods Immunocompetent mice were implanted with murine glioma cell lines and the role of astrocyte in the tumor pathogenicity was analyzed, and further investigated using in-vitro co-cultures. Results Here we report that depletion of reactive astrocytes regresses glioblastoma and prolongs mouse survival. Analysis of the tumor-associated astrocyte translatome, revealed that astrocytes initiate transcriptional programs that shape the immune and metabolic compartments in the glioma microenvironment. Specifically, their expression of CCL2 and CSF1 governs the recruitment of tumor-associated macrophages and promotes a pro-tumorigenic macrophage phenotype. Concomitantly, we demonstrate that astrocyte-derived cholesterol is key to glioma cell survival, and that targeting astrocytic cholesterol efflux, via ABCA1, halts tumor progression. In summary, astrocytes control glioblastoma pathogenicity by reprogramming the immunological properties of the tumor microenvironment and supporting the non-oncogenic metabolic dependency of glioblastoma on cholesterol. Conclusion These findings suggest that targeting astrocyte immunometabolic signaling may help treat this uniformly lethal brain tumor.

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Becker, Hannes, Justyna M. Przystal, Denis Canjuga, Foteini Tsiami, Nicole Anderle, Anna-Lena Keller, Anja Pohl et al. "TAMI-34. TARGETING CSF1R AND PD1 IN EXPERIMENTAL GLIOMA". Neuro-Oncology 23, Supplement_6 (2 de noviembre de 2021): vi205. http://dx.doi.org/10.1093/neuonc/noab196.818.

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Abstract The treatment of glioblastoma remains a challenge. Novel therapeutic strategies are urgently needed. Targeting the immunosuppressive glioblastoma-associated microenvironment is an interesting approach in this regard. Tumor-associated macrophages represent a distinct population of tumor-infiltrating immune cells with tumor-promoting features. The colony stimulating factor-1/ colony stimulating factor-1 receptor (CSF-1/CSF1R) axis plays an important role for macrophage differentiation and survival inside the tumor microenvironment. We thus aimed at investigating the antiglioma activity of CSF1R inhibition alone or in combination with blockade of programmed death (PD) 1. We detected CSF1R expression in paired tissue samples of primary and corresponding progressive glioblastoma. We investigated anti-CSF1R treatment alone or in combination with anti-PD1 antibodies in the orthotopic syngeneic VM/Dk SMA560 glioma mouse model, evaluated post-treatment effects and assessed treatment-induced cytotoxicity in a coculture model of patient-derived microtumors (PDM) and autologous tumor-infiltrating lymphocytes (TILs) ex vivo. Anti-CSF1R monotherapy increased the latency until the onset of neurological symptoms. Combinations of anti-CSF1R and anti-PD1 antibodies prolonged the latency until the onset of neurological symptoms and led to long-term survivors in vivo. Immunohistochemical analysis of post-treatment SMA-560 glioma revealed a modulation of the microenvironment, including increased T cell infiltration and reduced numbers of tumor-associated macrophages. Furthermore, we observed treatment-induced cytotoxicity of combined anti-CSF1R and anti-PD1 treatment in the PDM/TILs cocultures ex vivo. Taken together, our data indicates that CSF1R is a promising therapeutic target for glioblastoma, potentially in combination with PD1 inhibition.

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Pfleiderer, Kira, Verena Turco, Natalie K. Horvat, Jessica Hunger, Kianush Karimian-Jazi, Katharina Schregel, Gianluca Brugnara et al. "NIMG-48. TLR7/8-AGONIST-LOADED NANOPARTICLES REPROGRAM TUMOR-ASSOCIATED MYELOID CELLS FOR EFFECTIVE IMMUNOTHERAPY OF EXPERIMENTAL GLIOMA AND MRI-BASED TREATMENT MONITORING". Neuro-Oncology 23, Supplement_6 (2 de noviembre de 2021): vi139—vi140. http://dx.doi.org/10.1093/neuonc/noab196.546.

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Abstract Drivers of glioblastoma progression include the immunosuppressive tumor microenvironment (TME), dominated by tumor-associated myeloid cells. Therefore, we investigated a new approach targeting the myeloid compartment to reprogram myeloid cells in the TME using a β-cyclodextrin nanoparticle (CDNP) formulation encapsulating the toll-like receptor 7 and 8 (TLR7/8) agonist R848. Biodistribution confirmed specific targeting of CDNP-R848 to tumor-associated macrophages (TAMs) (labeling efficiency: 34.0% ± 22.2%), whereas tumor microglia (5.4% ± 4.4%) and splenic macrophages (13.2% ± 0.7%) revealed less uptake. Interestingly, intravenous application of CDNP-R848 induced strong tumor regression with an overall response rate of 80% (2.5% complete response, 52.5% partial response and 25% stable disease, n=40 mice) in Gl261 syngeneic experimental gliomas, while CDNP vehicle treated animals showed exponential tumor growth (100% progressive disease, n=12 mice). As advanced imaging is essential to monitor intracranial disease and possibly predict response and resistance, we performed high resolution magnetic resonance imaging using ultrasmall iron oxide nanoparticles (USPIO) for macrophage tracking. Increased levels of USPIO uptake in vehicle treated animals compared to CDNP-R848 treated animals were found as an early marker of responding mice (ΔT2*: -11.7 ± 4.2 vs -4.0 ± 2.8 ms, p=0.01). This correlated with an increased influx of myeloid cells into the TME of vehicle treated animals and showed a strong correlation of macrophage recruitment and USPIO uptake (R2: 0.78, p=0.004). Mechanistically, phenotyping of macrophages (CD45high/CD11b+) indicated a pro-inflammatory shift of TAMs with an increased infiltration of pro-inflammatory F4/80+/MHCII+ macrophages during CDNP-R848 treatment. Surprisingly, the anti-tumor effect of CDNP-R848 was independent of CD8+ T cells, CD4+ T cells or NK cells during selective depletion experiments. In summary, this work demonstrates the ability of myeloid-targeted therapies to re-shape the tumor microenvironment for an effective immunotherapy of glioma.

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Radin, Daniel P. y Stella E. Tsirka. "Interactions between Tumor Cells, Neurons, and Microglia in the Glioma Microenvironment". International Journal of Molecular Sciences 21, n.º 22 (11 de noviembre de 2020): 8476. http://dx.doi.org/10.3390/ijms21228476.

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Despite significant strides made in understanding the pathophysiology of high-grade gliomas over the past two decades, most patients succumb to these neoplasias within two years of diagnosis. Furthermore, there are various co-morbidities associated with glioma and standard of care treatments. Emerging evidence suggests that aberrant glutamate secretion in the glioma microenvironment promotes tumor progression and contributes to the development of co-morbidities, such as cognitive defects, epilepsy, and widespread neurodegeneration. Recent data clearly illustrate that neurons directly synapse onto glioma cells and drive their proliferation and spread via glutamatergic action. Microglia are central nervous system-resident myeloid cells, modulate glioma growth, and possess the capacity to prune synapses and encourage synapse formation. However, current literature has yet to investigate the potential role of microglia in shaping synapse formation between neurons and glioma cells. Herein, we present the literature concerning glutamate’s role in glioma progression, involving hyperexcitability and excitotoxic cell death of peritumoral neurons and stimulation of glioma proliferation and invasion. Furthermore, we discuss instances in which microglia are more likely to sculpt or encourage synapse formation during glioma treatment and propose studies to delineate the role of microglia in synapse formation between neurons and glioma cells. The sex-dependent oncogenic or oncolytic actions of microglia and myeloid cells, in general, are considered in addition to the functional differences between microglia and macrophages in tumor progression. We also put forth tractable methods to safely perturb aberrant glutamatergic action in the tumor microenvironment without significantly increasing the toxicities of the standard of care therapies for glioma therapy.

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Akkari, Leila, Robert L. Bowman, Jeremy Tessier, Florian Klemm, Shanna M. Handgraaf, Marnix de Groot, Daniela F. Quail et al. "Dynamic changes in glioma macrophage populations after radiotherapy reveal CSF-1R inhibition as a strategy to overcome resistance". Science Translational Medicine 12, n.º 552 (15 de julio de 2020): eaaw7843. http://dx.doi.org/10.1126/scitranslmed.aaw7843.

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Tumor-associated macrophages (TAMs) and microglia (MG) are potent regulators of glioma development and progression. However, the dynamic alterations of distinct TAM populations during the course of therapeutic intervention, response, and recurrence have not yet been fully explored. Here, we investigated how radiotherapy changes the relative abundance and phenotypes of brain-resident MG and peripherally recruited monocyte-derived macrophages (MDMs) in glioblastoma. We identified radiation-specific, stage-dependent MG and MDM gene expression signatures in murine gliomas and confirmed altered expression of several genes and proteins in recurrent human glioblastoma. We found that targeting these TAM populations using a colony-stimulating factor–1 receptor (CSF-1R) inhibitor combined with radiotherapy substantially enhanced survival in preclinical models. Our findings reveal the dynamics and plasticity of distinct macrophage populations in the irradiated tumor microenvironment, which has translational relevance for enhancing the efficacy of standard-of-care treatment in gliomas.

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Yalcin, Fatih, Alice Buonfiglioli, Ibrahim Efecan Efe, Hannah Haneke, Leonard D. Kuhrt, Michael Synowitz, Bernadette Nickl, Michael Bader, Helmut Kettenmann y Omar Dzaye. "TMIC-30. MICROGLIA/BRAIN MACROPHAGES PROMOTE GLIOMA GROWTH BY EXPRESSING GLYCOPROTEIN NMB". Neuro-Oncology 21, Supplement_6 (noviembre de 2019): vi254. http://dx.doi.org/10.1093/neuonc/noz175.1064.

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Abstract BACKGROUND Glioma-associated microglia and blood-derived macrophages (GAMs) promote tumor growth in experimental mouse glioma models. Using microarray and RNA sequencing, we have previously shown that GAMs upregulate the expression of Glycoprotein NMB/Osteoactivin (GPNMB) when compared to naïve microglia. GPNMB is a type 1 transmembrane glycoprotein expressed intracellularly under healthy conditions. Malignancies such as glioma induce a translocation into the plasma membrane where the extracellular domain can be cleaved and released. METHODS We used qRT-PCR, immunocytochemistry, Western Blot and flow cytometry to determine the cellular localization of GPNMB expression in human and mouse glioblastoma. To test the impact of microenvironment-derived GPNMB on glioma growth, we inoculated GL261 and RCAS-PDGFb glioblastoma cells into organotypic brain slices obtained from wildtype and GPNMB-/- mice. In addition, we quantified glioma growth after injection of RCAS-PDGFb cells into wildtype and GPNMB-/- mice. The soluble extracellular domain of GPNMB was used to stimulate primary human glioblastoma and RCAS-PDGFb cells in vitro. SRB assays were performed to assess proliferation. RESULTS Our data indicate that GAMs are the predominant source of GPNMB in both human and mouse glioblastoma and that the levels of expression in GAMs in the tumor microenvironment is higher than in naïve microglia. In the organotypic brain slice model we found that tumors were significantly smaller in slices derived from GPNMB-/- mice as compared to wildtype. The tumor growth in vivo was nearly completely blocked in the absence of GPNMB. Stimulation of glioma cells with the extracellular domain of GPNMB did not increase proliferation. CONCLUSION Our results show that GPNMB is predominantly expressed in GAMs of human and murine samples. Loss of GPNMB impaired tumor growth ex vivo and glioblastoma progression in vivo. GPNMB seems to play a crucial role in the pro-tumorigenic activity of microglia and blood-derived macrophages in the tumor microenvironment.

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Jang, Bum-Sup y In Ah Kim. "TAMI-32. CORRELATION BETWEEN RADIOSENSITIVITY INDEX AND M2 MACROPHAGE PROPORTION IN TUMOR MICROENVIRONMENT OF GLIOBLASTOMA". Neuro-Oncology 23, Supplement_6 (2 de noviembre de 2021): vi204—vi205. http://dx.doi.org/10.1093/neuonc/noab196.816.

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Abstract BACKGROUND Tumor-associated macrophages (TAMs) Macrophage are predominant in glioblastoma tumor microenvironment (TME), supporting for neoplastic cell expansion and invasion. We investigated the relationship between radiosensitivity of glioblastoma and M1/M2 macrophage profiles in bulk and single cell RNA sequencing datasets. METHODS We used radiosensitivity index (RSI) gene signature and estimated RSI score based on the ranking of genes by expression level. Two large glioma datasets – The Cancer Genome Atlas (TCGA) and Chinese Glioma Genome Atlas (CGGA) – were employed to identify whether RSI is clinically predictive of overall survival following radiation therapy. To analyze the association between M1/M2 macrophages and RSI within spatial context, the Ivy Glioblastoma Atlas Project dataset was investigated and single cell RNA sequencing dataset (GSE84465) was analyzed as well. Macrophages were profiled using a deconvolution algorithm, CIBERSORTx. RESULTS The RSI-high group having radioresistant tumors showed worse overall survival than the RSI-low group in both the TCGA (HR=1.87, 95% CI=1.06-3.29, P=0.031) and the CGGA (HR=1.61, 95% CI=1.04-2.50, P=0.031) glioblastoma population. In the Ivy Glioblastoma Atlas Project dataset, radiosensitive tumor having lower RSI was significantly more found in more vascular region including hyperplastic and microvascular region (coefficient=-0.07, P=0.001), meanwhile, radioresistant tumor was significantly clustered in necrotic region including perinecrotic and pseudopalisading regions (coefficient=0.07, P< 0.001). The proportion of M1/M2 macrophage and RSI score showed an inverse relationship (coefficient=-0.23, P=0.015), indicating that radioresistant glioblastomas are related with TME having more M2 than M1 macrophage. In single cell RNA sequencing dataset composed of immune and tumor cells collected from four patients, mean RSI of neoplastic cells was positively correlated with high proportion of M2 macrophages. CONCLUSION RSI can predict radiation response in terms of overall survival in glioblastoma patients. High proportion of M2 macrophage may play an important role in TME of radioresistant glioblastoma.

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Su, Yu-Ting, Madison Butler, Lee Hwang, Dragan Maric, Shelton Earp, Masaki Terabe, Mark Gilbert y Jing Wu. "EXTH-44. INHIBITION OF MerTK ACTIVATES GLIOBLASTOMA-ASSOCIATED MACROPHAGES AND INDUCES TUMOR CELL DEATH IN GLIOMA MICROENVIRONMENT". Neuro-Oncology 21, Supplement_6 (noviembre de 2019): vi91. http://dx.doi.org/10.1093/neuonc/noz175.376.

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Abstract BACKGROUND Glioblastoma-associated macrophages and microglia (GAMs) are the predominant immune cells in the tumor microenvironment. Activation of MerTK, a receptor tyrosine kinase, triggers efferocytosis and polarizes GAMs to an immunosuppressive phenotype, promoting glioma growth. Our previous findings showed that UNC2371, a small-molecule inhibitor of MerTK, induced a less immunosuppressive phenotype of GAMs. Here, we investigate the role of MerTK inhibition on glioblastoma cells in the tumor microenvironment in vitro and in vivo. METHODS Cytotoxicity of UNC2371 in glioblastoma cells was determined by cell viability and colony formation assays. The protein expression of MerTK, AKT, and Erk were quantified by Western blotting in UNC2371-treated glioblastoma cells. A syngeneic GL261 mouse orthotopic glioblastoma model was used to evaluate the survival benefit of UNC2371 treatment. Fluorescent multiplex immunohistochemistry (IHC) was used to evaluate the expression of CD206, an anti-inflammatory marker on GAMs in murine brain tumor tissues. RESULTS UNC2371 inhibited GBM cell growth with an EC50 < 100 nM in both human U251 and mouse GL261 glioma cells, but not in GAMs. UNC2371-induced cell death and decreased cell proliferation were demonstrated by colony formation assays. UNC2371 decreased protein expression of phosphorylated MerTK, AKT, and Erk, which are essential for cell survival signaling, in U251 and GL261 cells. Furthermore, UNC2371 treatment prolonged survival in the mouse orthotopic GL261 glioblastoma model, suggesting that UNC2371 induces glioma cell death. A decreased of CD206+ GAMs was found in mice glioma tissues by fluorescent multiplex IHC, consistent with our previous findings in the in vitro cell-based assays. These data suggest that in addition to alleviate immunosuppression in the glioma microenvironment, UNC2371 directly inhibits GBM cell growth in vitro and in vivo. CONCLUSION Our findings suggest that UNC2371 has a therapeutic benefit via promoting GAM polarization towards proinflammatory status in the glioblastoma microenvironment and unexpectedly, inducing tumor cell death.

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Abdelfattah, Nourhan, Jose Maldonado, Jia-Shiun Liu, Nhat Tran y Kyuson Yun. "TMIC-63. SELECTIVE TARGETING OF IMMUNE-SUPPRESSIVE LEUKOCYTES TO REPROGRAM THE GBM IMMUNE LANDSCAPE". Neuro-Oncology 24, Supplement_7 (1 de noviembre de 2022): vii285. http://dx.doi.org/10.1093/neuonc/noac209.1107.

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Abstract A significant barrier to immunotherapy efficacy is GBM’s immunosuppressive microenvironment composed of few tumor-infiltrating lymphocytes (TILs; < 5%) but abundant myeloid cells, making it an “immune cold” tumor. To enhance immunotherapy efficacy, a better molecular and functional understanding of the heterogeneous cell types in the GBM microenvironment and their function is urgently needed. Single cell RNA-sequencing offers high-resolution cellular and molecular data to elucidate cancer and stromal cell phenotypes at the single cell level to identify the most relevant cell types to target to enhance immune activation. We recently reported an integrated, multi-regional and -dimensional single-cell transcriptomic analysis of 201,986 human glioma and immune cells derived from 44 tissue fragments from 18 human glioma patients. In doing so, we mapped GBM cellular heterotypia and spatial, molecular, and functional heterogeneity of glioma associated immune cells. We observed an extensive spatial and molecular heterogeneity of glioma cells, microglia, macrophages, and T cells within the same tumor samples in low-grade gliomas (LGGs), primary GBMs, and recurrent GBMs. Importantly, our analysis of 83,479 glioma infiltrating myeloid cells identifies 9 molecularly distinct myeloid subtypes: 4 microglia, 4 bone marrow-derived macrophage (BMDM), and dendritic cell subtypes. Importantly, five of these myeloid cell subtype gene signatures were independent predictors of patient survival in multiple datasets, demonstrating the importance of immune cells in disease progression and aggressiveness. Here, we report evidence for heterogeneous cell:cell communication between glioma and immune cells in different regions within a patient, using CellChat, Cellphone DB, and NicheNet tools. We also nominate immune modulators other than PD1/PDL1 and CTLA3 as more promising targets in GBM. Finally, we provide evidence that S100A4 is a promising novel immunotherapy target since its high-level expression is required for immune-suppressive macrophages and Tregs to block T cell infiltration and DC maturation.

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Ostrom, Quinn, Joanne Xiu, Giselle lopez, Ashley Sumrall, Sonikpreet Aulakh, Michael Glantz, Edward Pan, Mustafa Khasraw, David M. Ashley y Kyle Walsh. "BIOM-17. DIFFERENCES IN THE IMMUNE MICROENVIRONMENT OF GLIOMAS HARBORING IDH2 VERSUS IDH1 MUTATIONS". Neuro-Oncology 23, Supplement_6 (2 de noviembre de 2021): vi13—vi14. http://dx.doi.org/10.1093/neuonc/noab196.048.

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Abstract INTRODUCTION IDH mutations are a defining feature of lower-grade glioma and secondary glioblastoma. Approximately 95% of glioma-associated IDH mutations are in codon 132 of IDH1, but a small proportion are in IDH2. IDH mutations produce the oncometabolite 2-hydroxyglutarate, which induces global DNA hypermethylation and is associated with an immunosuppressive tumor microenvironment. IDH1 is localized in the cytosol while IDH2 is found in the mitochondrial matrix, and mutations in these genes may have differing effects on the tumor microenvironment. METHODS Formalin-fixed, paraffin-embedded tissue from 633 IDH-mutant gliomas (615 IDH1-mutant, 18 IDH2-mutant) underwent whole-exome and whole-transcriptome sequencing at Caris Life Sciences (236 grade 2/3 astrocytoma, 158 grade 2/3 oligodendroglioma, 202 IDH-mutant glioblastoma, 37 glioma, NOS). QuantiSEQ was used to infer tumor-infiltrating immune cell populations from RNAseq data, and gene-set enrichment analyses (GSEA) were performed using Wikipathway. RESULTS IDH1-mutant gliomas had higher levels of pro-inflammatory M1 macrophages (P=0.04), modestly higher levels of monocytes (P=0.08), and lower levels of neutrophils (P=0.04) – typically considered immunosuppressive – compared with IDH2-mutant gliomas. No differences were observed in levels of B cells, dendritic cells, NK cells, or T cell subsets (Treg, CD4+, CD8+). IDH2-mutant gliomas were enriched for hallmark oligodendroglioma mutations (TERT promoter, CIC, FUBP1), while IDH1-mutant gliomas were enriched for hallmark astrocytoma mutations (ATRX, TP53). However, associations with tumor-infiltrating immune cells persisted after excluding 1p/19q co-deleted oligodendroglioma from analyses. GSEA revealed upregulation of the microglial TYROBP signaling pathway, the microglial phagocytic pathway, and of Type II Interferon signaling in IDH1-mutant gliomas versus IDH2-mutant gliomas. CONCLUSIONS Although IDH2 mutations are generally thought to function similarly to IDH1 mutations, we observe differences in tumor-infiltrating immune cells across groups. IDH2-mutant gliomas appeared to have a more immunosuppressive tumor microenvironment than their IDH1-mutant counterparts. Early-phase immunotherapy trials should consider covariate-adaptive randomization approaches to equally allocate IDH2-mutant gliomas across treatment arms.

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Zheng, Zening, Jiaxin Zhang, Jizong Jiang, Yang He, Wenyuan Zhang, Xiaopeng Mo, Xuejia Kang, Qin Xu, Bing Wang y Yongzhuo Huang. "Remodeling tumor immune microenvironment (TIME) for glioma therapy using multi-targeting liposomal codelivery". Journal for ImmunoTherapy of Cancer 8, n.º 2 (agosto de 2020): e000207. http://dx.doi.org/10.1136/jitc-2019-000207.

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BackgroundGlioblastoma (GBM) treatment is undermined by the suppressive tumor immune microenvironment (TIME). Seek for effective methods for brain TIME modulation is a pressing need. However, there are two major challenges against achieving the goal: first, to screen the effective drugs with TIME-remodeling functions and, second, to develop a brain targeting system for delivering the drugs.MethodsIn this study, an α7 nicotinic acetylcholine receptors (nAChRs)-binding peptide DCDX was used to modify the codelivery liposomes to achieve a ‘three-birds-one-stone’ delivery strategy, that is, multi-targeting the glioma vessel endothelium, glioma cells, and tumor-associated macrophages that all overexpressed α7 nAChRs. A brain-targeted liposomal honokiol and disulfiram/copper codelivery system (CDX-LIPO) was developed for combination therapy via regulating mTOR (mammalian target of rapamycin) pathway for remodeling tumor metabolism and TIME. Honokiol can yield a synergistic effect with disulfiram/copper for anti-GBM.ResultsIt was demonstrated that CDX-LIPO remarkably triggered tumor cell autophagy and induced immunogenic cell death, and meanwhile, activated the tumor-infiltrating macrophage and dendritic cells, and primed T and NK (natural killer) cells, resulting in antitumor immunity and tumor regression. Moreover, CDX-LIPO promoted M1-macrophage polarization and facilitated mTOR-mediated reprogramming of glucose metabolism in glioma.ConclusionThis study developed a potential combinatory therapeutic strategy by regulation of TIME and a ‘three-birds-one-stone’-like glioma-targeting drug delivery system.

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Canella, Alessandro, Matthew Nazzaro, Claire Schmitt, Sakthi Rajendran, Abigail Haffey, Giovanni Nigita, Diana Thomas y Prajwal Rajappa. "EXTH-97. BONE MARROW-DERIVED ENGINEERED MYELOID CELLS ENHANCE THE TRAFFICKING AND ACTIVATION OF CYTOTOXIC T CELLS IN THE GLIOMA MICROENVIRONMENT". Neuro-Oncology 24, Supplement_7 (1 de noviembre de 2022): vii232. http://dx.doi.org/10.1093/neuonc/noac209.895.

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Abstract INTRODUCTION Gliomas are the most prevalent type of brain tumors in the adolescent and young adult population (AYA) and one of the leading causes of cancer- related death. Two-third of glioma AYA patients are affected by low-grade gliomas (LGGs), but yet there are no specific treatments. Therefore, a significant percentage of LGG patients experience tumor recurrence and malignant progression to high-grade glioma (HGG) and the immune microenvironment plays a critical role in mediating mechanisms of tumor progression and treatment resistance. Specifically, tumor associated macrophages (TAMs) and myeloid-derived suppressor cells (MDSCs) have been shown to restrict cytotoxic effector trafficking and activation. To that end, first-line immunotherapies have limited efficacy in improving outcomes for HGGs. HYPOTHESIS We investigated the preclinical efficacy of a novel immunotherapeutic approach for the treatment of LGGs in AYA mice to modulate and reprogram the immunosuppressive tumor microenvironment (TME) and enhance the trafficking of activated effector T cells. METHODS Immunocompetent RCAS n/tv-a LGG bearing animals were treated at day 28 with a single retroorbital dose of bone-marrow derived myeloid cells, engineered for the release of Interlekin-2 (GEMys-IL2). The treatment was well tolerated and no sign of toxicity was noted. RESULTS Our results demonstrated that GEMys-IL2 efficiently crossed the BBB, infiltrate the glioma microenvironment, and activate infiltrating immune cells while altering the TME underscored by an increased CD8+ T cell population. Of note, the RCAS/t-va immunocompetent LGG to HGG progression mouse model treated with a single dose of GEMys-IL2 demonstrated a transient arrest of tumor burden within 14 days post treatment, which was associated with a significant advantage in overall survival. CONCLUSIONS These results highlight the pre-clinical efficacy and anti-tumoral therapeutic activity of GEMYys-IL2 on CD8+ T cell trafficking and activation to the TME in low-grade glioma in vivo, thus supporting its potential as a novel cell-mediated innate immunotherapy.

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Li, Lin, Leyang Wu, Xingpeng Yin, Chenyang Li y Zichun Hua. "Bulk and Single-Cell Transcriptome Analyses Revealed That the Pyroptosis of Glioma-Associated Macrophages Participates in Tumor Progression and Immunosuppression". Oxidative Medicine and Cellular Longevity 2022 (26 de septiembre de 2022): 1–35. http://dx.doi.org/10.1155/2022/1803544.

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Glioma is the most common of all central nervous system (CNS) malignancies and is associated with a poor prognosis. Pyroptosis has been proven to be associated with the progression of multiple tumors and CNS diseases. However, the relationships between pyroptosis and clinical prognosis and immune cell infiltration are unclear in glioma. In this study, we conducted a comprehensive exploration of pyroptosis in glioma. First, prognosis-related genes were screened at each key regulatory locus in the pyroptosis pathway, and the prognostic ability and coexpression relationships of GSDMD and its upstream pathway genes NLRC4/CASP1/CASP4 were identified and well validated in multiple datasets. Tissue microarray-based immunohistochemistry results showed higher levels of NLRC4 and N-terminal GSDMD in high-grade gliomas, providing conclusive evidence of pyroptosis in gliomas. The robustness of the prognostic model based on these four genes was well validated in TCGA and CGGA cohorts. Bulk RNA-seq-based analysis showed that the group defined as the high-risk group according to the model showed activation of multiple inflammatory response pathways and impaired synaptic gene expression and had a higher infiltration of bone marrow-derived macrophages (BMDMs) and a hypersuppressed immune microenvironment. More importantly, three independent single-cell RNA-seq (scRNA-seq) datasets demonstrated that tumor-infiltrating macrophages, particularly BMDMs but not tissue-resident microglia, showed significant coexpression of the GSDMD and CASP genes, and BMDMs from high-grade gliomas accounted for a higher proportion of immune infiltrating cells and had higher expression of pyroptosis genes. Finally, we revealed the activation of pathways in response to LPS/bacteria and oxidative stress during BMDM development toward the pyroptosis cell fate by pseudotime trajectory analysis, suggesting potential BMDM pyroptosis initiators. The above results provide not only novel insights into the pathological mechanisms of glioma but also novel therapeutic targets for glioma, suggesting the potential application of pyroptosis inhibitors (e.g., disulfiram).

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Kumar, Anupam, Katharine Chen, Claudia Petritsch, Theodore Nicolaides, Mariarita Santi-Vicini, Arie Perry, Andrew Bollen, David Solomon, Annette M. Molinaro y Joanna Phillips. "TAMI-07. THE IMMUNE MICROENVIRONMENT IN LOWER GRADE GLIOMAS". Neuro-Oncology 22, Supplement_2 (noviembre de 2020): ii214. http://dx.doi.org/10.1093/neuonc/noaa215.896.

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Abstract The determinants of the tumor-associated immune response in brain tumors are poorly understood. Using tumor samples from two molecularly distinct subtypes of lower grade glioma, MAPK-driven glioma with biallelic inactivation of CDKN2A (n=30) and IDH-mutant, 1p/19q-intact astrocytoma (n=29), we demonstrate qualitative and quantitative differences in the tumor-associated immune response and we investigate the molecular mechanisms involved. Histologically the MAPK-driven gliomas were comprised of pleomorphic xanthoastrocytoma (PXA) (n=11) and anaplastic PXA (n=19). Seven patients had paired samples from two sequential surgeries. Immune cell populations and their activity were determined by quantitative multiplex immunostaining and Digital Spatial Profiling and gene expression was analyzed by Nanostring. Functional studies were performed using established cell lines and two new patient-derived lines from MAPK-driven LGGs. MAPK-driven tumors exhibited an increased number of CD8+ T cells and tumor-associated microglial/macrophage (TAMs), including CD163+ TAMs, as compared to IDH-mutant astrocytoma. In contrast, IDH-mutant tumors had increased FOXP3+ immunosuppressive T regulatory cells. Transcriptional and protein level analyses in MAPK-driven tumors suggested an active cytotoxic T cell response with robust expression of granzyme B, present on 27% of CD8+ T cells, increased MHC class I expression, and altered cytokine profiles. Interestingly, MAPK-driven tumors also had increased expression of immunosuppressive molecules, including CXCR4, PD-L1, and VEGFA. Expression differences for cell surface and secreted proteins were confirmed in patient-derived tumor lines and functional relationships between altered chemokine expression and immune cell infiltration was investigated. Our data provide novel insights into the immune contexture of MAPK driven LGGs and suggest MAPK driven gliomas with biallelic inactivation of CDKN2A may be particularly vulnerable to immunotherapeutic modulation

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Tsutsui, Taishi, Hironori Kawahara, Ryouken Kimura, Yu Dong, Shabierjiang Jiapaer, Hemragul Sabit, Jiakang Zhang, Takeshi Yoshida, Mitsutoshi Nakada y Rikinari Hanayama. "Glioma-derived extracellular vesicles promote tumor progression by conveying WT1". Carcinogenesis 41, n.º 9 (28 de mayo de 2020): 1238–45. http://dx.doi.org/10.1093/carcin/bgaa052.

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Abstract Glioma persists as one of the most aggressive primary tumors of the central nervous system. Glioma cells are known to communicate with tumor-associated macrophages/microglia via various cytokines to establish the tumor microenvironment. However, how extracellular vesicles (EVs), emerging regulators of cell–cell communication networks, function in this process is still elusive. We report here that glioma-derived EVs promote tumor progression by affecting microglial gene expression in an intracranial implantation glioma model mouse. The gene expression of thrombospondin-1 (Thbs1), a negative regulator of angiogenesis, was commonly downregulated in microglia after the addition of EVs isolated from different glioma cell lines, which endogenously expressed Wilms tumor-1 (WT1). Conversely, WT1-deficiency in the glioma-derived EVs significantly attenuated the Thbs1 downregulation and suppressed the tumor progression. WT1 was highly expressed in EVs obtained from the cerebrospinal fluid of human patients with malignant glioma. Our findings establish a novel model of tumor progression via EV-mediated WT1–Thbs1 intercellular regulatory pathway, which may be a future diagnostic or therapeutic target.

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Bockmary, Michael, Frederick Klauschen, Cecile Maire, Stefan Rutkowski, Manfred Westphal, Katrin Lamszus, Ulrich Schüller y Malte Mohme. "PATH-53. IMMUNOLOGICAL PROFILING OF MUTATIONAL AND TRANSCRIPTIONAL SUBGROUPS IN PEDIATRIC AND ADULT HIGH-GRADE GLIOMAS". Neuro-Oncology 21, Supplement_6 (noviembre de 2019): vi155. http://dx.doi.org/10.1093/neuonc/noz175.648.

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Abstract Immunological treatment strategies, including checkpoint inhibition, are currently under investigation for high-grade gliomas, but their success is limited. Hence, it is crucial to determine immunological pathways that can be targeted and to identify subgroups of patients likely to benefit from immunotherapies. Previous studies are still limited by comparably small sample sizes and there is only few data about specific immunological mechanisms in pediatric high-grade glioma. We gathered published gene expression data from 1135 adult and pediatric high-grade gliomas and applied a machine learning technique to determine their mutational (K27, G34, IDHmut, IDHwt) and transcriptional subtype. Subsequently, immune cell infiltration and functional immune pathway signatures were evaluated in correlation to histological diagnosis, age, transcriptional and mutational subtype. T-SNE analysis and unsupervised hierarchical clustering was applied to detect subgroup-specific immune microenvironments across all high-grade glioma subtypes. Four distinct microenvironmental phenotypes of immune cell infiltration were identified, which can be stratified into vascular, monocytic/stromal, monocytic/T-cell and APC/NK/T-cell dominant immune clusters. Immune cell infiltration correlated strongly with transcriptional and mutational subtypes but was independent of age and histological diagnosis (p< 0.01). H3F3A mutated tumors had significantly fewer tumor infiltrating lymphocytes and macrophages. By including functional pathways and correlating the expression of immunostimulatory and inhibitory receptor/ligand interactions, we were able to define the immunological microenvironment and to identify possible immunological subtypes associated with poor prognosis as well as subtypes that might be especially amenable to checkpoint inhibition. In addition, comparisons of overall survival with the immunological microenvironment and specifically with immune checkpoint molecules revealed diverse correlations within the transcriptional and mutational subgroups. In conclusion, we shat that mutational and transcriptional subgroups of pediatric and adult high-grade gliomas are characterized by distinct immunological tumor microenvironments. Our analysis demonstrates the immunological heterogeneity within this entity and emphasizes an immune specific stratification of subgroups for upcoming immunotherapy trials.

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Sanders, Stephanie, Denise M. Herpai, Analiz Rodriguez, Yue Huang, Jeff Chou, Fang-Chi Hsu, Darren Seals, Ryan Mott, Lance D. Miller y Waldemar Debinski. "The Presence and Potential Role of ALDH1A2 in the Glioblastoma Microenvironment". Cells 10, n.º 9 (20 de septiembre de 2021): 2485. http://dx.doi.org/10.3390/cells10092485.

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Glioblastoma (GBM) is the most aggressive malignant glioma. Therapeutic targeting of GBM is made more difficult due to its heterogeneity, resistance to treatment, and diffuse infiltration into the brain parenchyma. Better understanding of the tumor microenvironment should aid in finding more effective management of GBM. GBM-associated macrophages (GAM) comprise up to 30% of the GBM microenvironment. Therefore, exploration of GAM activity/function and their specific markers are important for developing new therapeutic agents. In this study, we identified and evaluated the expression of ALDH1A2 in the GBM microenvironment, and especially in M2 GAM, though it is also expressed in reactive astrocytes and multinucleated tumor cells. We demonstrated that M2 GAM highly express ALDH1A2 when compared to other ALDH1 family proteins. Additionally, GBM samples showed higher expression of ALDH1A2 when compared to low-grade gliomas (LGG), and this expression was increased upon tumor recurrence both at the gene and protein levels. We demonstrated that the enzymatic product of ALDH1A2, retinoic acid (RA), modulated the expression and activity of MMP-2 and MMP-9 in macrophages, but not in GBM tumor cells. Thus, the expression of ALDH1A2 may promote the progressive phenotype of GBM.

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Varn, Frederick, Kevin Johnson, Floris Barthel, Hoon Kim, Taylor Wade, Disha Lodha, Shoaib Ajaib et al. "EPCO-08. TUMOR-IMMUNE INTERACTIONS ARE DYNAMIC AND INFLUENCE THE EVOLUTIONARY TRAJECTORY OF ADULT DIFFUSE GLIOMA". Neuro-Oncology 22, Supplement_2 (noviembre de 2020): ii70—ii71. http://dx.doi.org/10.1093/neuonc/noaa215.287.

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Abstract Diffuse glioma is an aggressive brain cancer that is characterized by a poor prognosis and a universal resistance to therapy. The evolutionary processes behind this resistance remain unclear. Previous studies by the Glioma Longitudinal Analysis (GLASS) Consortium have indicated that therapy-induced selective pressures shape the genetic evolution of glioma in a stochastic manner. However, single cell studies have revealed that malignant glioma cells are highly plastic, and capable of changing their cell state in response to diverse challenges in their microenvironment. The tumor immune response has been implicated as a major driver of these malignant cell state transitions, and is known to be affected by the administration of therapy, but the extent to which tumor genetics, therapy, and the different components of the immune response interact to influence a glioma’s evolutionary trajectory are poorly understood. To further investigate these factors, we collected DNA and RNA sequencing data on pre- and post-treatment tumor pairs from over 150 glioma patients that have received chemotherapy, radiotherapy, and/or immune checkpoint blockade agents. By integrating mutation, copy number, and in silico deconvolution analyses of bulk transcriptome data across the three molecular subtypes of diffuse glioma, we show that longitudinal increases in chromosomal instability and gene fusions associate with decreased immune infiltrate and altered cell states at recurrence. We additionally find that specific molecular alterations and malignant cell states associate with unique inflammatory and immunosuppressive programs in tumor-associated macrophages and microglia. Lastly, we show that the abundance of T cells in the tumor microenvironment does not associate with changes in neoantigen depletion and the acquisition of antigen presentation machinery defects, suggesting minimal immunoediting activity over time. Collectively, our results indicate that the administration of therapy can alter the dynamics of tumor-immune interactions in glioma, resulting in new steady-states at recurrence that can be subsequently targeted.

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Devaraja, Kaviya, Sheila Mansouri y Gelareh Zadeh. "BSCI-14 THE ROLE OF ICAM1 IN GLIOBLASTOMA TUMOUR ASSOCIATED MACROPHAGES UNDER HYPOXIC CONDITIONS". Neuro-Oncology Advances 4, Supplement_1 (1 de agosto de 2022): i3—i4. http://dx.doi.org/10.1093/noajnl/vdac078.013.

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Abstract BACKGROUND Glioblastoma (GBM) is an aggressive and highly fatal brain cancer in adults. Existing treatment methods are ineffective and we are in need of new treatments that extend the overall survival and improve quality-of-life. Cell adhesion molecules (CAMs) are proteins that enable cells to communicate with one another and the surrounding environment. Intracellular adhesion molecule 1 (ICAM1) is a CAM expressed by TAMs in GBM. Tumour associated macrophages (TAMs) are thought to enhance tumour growth and proliferation, particularly within the characteristic hypoxic tumour microenvironment (TME) of GBM. I hypothesize that the expression of ICAM1 on the surface of TAMs contributes to GBM cell invasiveness, especially in the hypoxic TME, by enhancing the interaction between tumour cells and macrophages, thereby facilitating the migration and invasion of the tumour cells. METHODOLOGY Assess the expression levels of ICAM1 in primary and immortalized human and mouse macrophages under hypoxic conditions. Analyze the effect of ICAM1 deficiency on macrophage behaviour including migration, proliferation, and adhesion to tumour cells. Intracranially inject GL261 glioma cells in ICAM1 deficient and wild type mice. RESULTS ICAM1 is highly expressed in different cell types within the GBM microenvironment, including TAMs. The expression is particularly enhanced when primary or immortalized macrophages are treated with tumour cell-conditioned medium and is further exacerbated upon incubation of these cells in hypoxic conditions. The migration levels of bone marrow derived macrophage mouse cell type is higher in wild type cells than in ICAM1 deficient cells and higher when co-cultured with tumour cell condition media. ICAM1 deficient mice succumbed to GBM more quickly compared with wild type. CONCLUSIONS It is evident that the hypoxic tumour microenvironment increases the expression of ICAM1 in macrophages. The tumour microenvironment increases migration levels of macrophages. The expression of ICAM1 in TAMs in hypoxic TME promotes GBM cell invasiveness, proliferation, aggressiveness and migration.

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Dzwigonska, Monika, Jakub Mieczkowski, Paulina Pilanc, Salwador Cyranowski, Agata Kominek, Katarzyna Piwocka, Bozena Kaminska y Katarzyna B. Leszczynska. "OTME-2. Regulation of chromatin accessibility in the hypoxic tumor microenvironment of glioblastoma". Neuro-Oncology Advances 3, Supplement_2 (1 de julio de 2021): ii13. http://dx.doi.org/10.1093/noajnl/vdab070.053.

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Abstract Chromatin structure is often dysregulated in cancers, including glioblastoma (GBM), the most common primary brain tumor in adults. GBM has the poorest prognosis and no efficient cure to date due to diffusive growth into the surrounding brain, preventing complete surgical resection and leading to inevitable tumor relapse. Tumor microenvironment (TME) of GBM contains brain-residing microglia and bone-marrow derived macrophages (collectively known as glioma-associated microglia/macrophages, GAMs) that constitute up to 30% of the tumor mass and promote tumor invasion. Hypoxia (a shortage of oxygen) is a key factor in tumor progression of GBM as it can globally and rapidly alter the gene expression, induce cancer cell invasiveness, stemness and lead to therapy resistance. Hypoxia can enhance the pro-tumorigenic function of GAMs, e.g. by inducing expression of cytokines and cell surface receptors both in GAMs and glioma cells, but little is known about chromatin alterations of GBM under hypoxia. Since regulation of expression of such molecules could depend on the epigenetic alterations, we hypothesize that hypoxia may potently alter the chromatin accessibility and functions of GAMs and glioma cells. We determine the genome-wide changes in chromatin accessibility in GAMs and glioma cells in response to hypoxic stress using single-cell Pi-ATAC-seq (Protein-indexed Assay of Transposase Accessible Chromatin with sequencing), which allows simultaneous genome-wide assessment of chromatin accessibility and expression of intracellular protein markers in single cells, allowing faithful selection of hypoxic and non-hypoxic cells. Secondly, we are employing an oxygen-dependent co-culture model in vitro to study the mechanisms of chromatin alterations in GAMs and glioma cells under controlled hypoxic conditions and test how these changes depend on the glioma - GAMs cross-communication. In summary, we characterize the interactions between innate immune cells and glioma cells by looking at their chromatin alterations under hypoxia. Supported by the National Science Center grant (Poland) 2019/33/B/NZ1/01556 (KBL).

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Markwell, Steven, Cheryl Olson, James Ross, Felix Nunez-Santana y Daniel Brat. "TAMI-56. HYPOXIA-DRIVEN NECROSIS DRIVES DYNAMIC TUMOR PROGRESSION IN GLIOBLASTOMA". Neuro-Oncology 22, Supplement_2 (noviembre de 2020): ii225. http://dx.doi.org/10.1093/neuonc/noaa215.943.

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Abstract The onset of necrosis correlates with aggressive malignant progression in solid tumors. Whether necrosis arises from or promotes accelerated tumor proliferation and progression remains unknown, primarily due to inadequate models systems that fail to induce or capture these dynamic changes as they develop. In glioblastoma (GBM; WHO grade IV), the most malignant primary brain tumor, vascular pathology and central necrosis precedes rapid, radial expansion resulting in patient mortality. While genetic alterations in GBM have been highly characterized, biological adaptations arising from sustained hypoxia/anoxia require further mechanistic investigation. This sustained nutrient deprivation leads to necrosis which dramatically changes the tumor microenvironment (TME). To reveal the dynamic temporal and spatial changes promoting expansive progression, we are generating mouse models that more appropriately capture events found in human gliomas, accounting for unique microenvironmental stressors often lacking in GBM animal models, specifically central necrosis. Combining hypoxia-induced focal necrosis within high grade gliomas with intravital microscopy captures TME restructuring to understand its impact on glioma progression. Our studies use both genetically characterized patient-derived orthotopic GBM xenografts, alongside an immunocompetent RCAS/tv-a model, to determine how antagonizing these processes impacts disease progression and outcomes across multiple GBM subtypes. Complementary to this, we are investigating how increasing hypoxia and necrosis-driven signaling events promotes tumor-associated macrophages (TAMs) influx and reprogramming during glioma progression. Our preliminary data indicate substantial differences pre- and post-necrosis regarding TAM enrichment, immunosuppressive phenotypic conversion and their biological impact, however these mechanisms have not yet been elucidated. Our models capture glioma growth dynamics, reactive neuroinflammation and therapeutic resistance, facilitating innovative pre-clinical interventions to improve patient outcome.

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Su, Yu-Ting, Funita Phan, Lee Hwang, H. Shelton Earp, Mark Gilbert y Jing Wu. "TMIC-32. INHIBITION OF MerTK MODULATES GLIOMA-ASSOCIATED MACROPHAGES AND MICROGLIA IN TUMOR MICROENVIRONMENT". Neuro-Oncology 20, suppl_6 (noviembre de 2018): vi263. http://dx.doi.org/10.1093/neuonc/noy148.1091.

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Zinnhardt, Bastian, Michael Müther, Wolfgang Roll, Philipp Backhaus, Astrid Jeibmann, Claudia Foray, Cristina Barca et al. "TSPO imaging-guided characterization of the immunosuppressive myeloid tumor microenvironment in patients with malignant glioma". Neuro-Oncology 22, n.º 7 (12 de febrero de 2020): 1030–43. http://dx.doi.org/10.1093/neuonc/noaa023.

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Abstract Background Tumor-associated microglia and macrophages (TAMs) and myeloid-derived suppressor cells (MDSCs) are potent immunosuppressors in the glioma tumor microenvironment (TME). Their infiltration is associated with tumor grade, progression, and therapy resistance. Specific tools for image-guided analysis of spatiotemporal changes in the immunosuppressive myeloid tumor compartments are missing. We aimed (i) to evaluate the role of fluorodeoxyglucose (18F)DPA-714* (translocator protein [TSPO]) PET-MRI in the assessment of the immunosuppressive TME in glioma patients, and (ii) to cross-correlate imaging findings with in-depth immunophenotyping. Methods To characterize the glioma TME, a mixed collective of 9 glioma patients underwent [18F]DPA-714-PET-MRI in addition to [18F]fluoro-ethyl-tyrosine (FET)-PET-MRI. Image-guided biopsy samples were immunophenotyped by multiparametric flow cytometry and immunohistochemistry. In vitro autoradiography was performed for image validation and assessment of tracer binding specificity. Results We found a strong relationship (r = 0.84, P = 0.009) between the [18F]DPA-714 uptake and the number and activation level of glioma-associated myeloid cells (GAMs). TSPO expression was mainly restricted to human leukocyte antigen D related–positive (HLA-DR+) activated GAMs, particularly to tumor-infiltrating HLA-DR+ MDSCs and TAMs. [18F]DPA-714–positive tissue volumes exceeded [18F]FET-positive volumes and showed a differential spatial distribution. Conclusion [18F]DPA-714-PET may be used to non-invasively image the glioma-associated immunosuppressive TME in vivo. This imaging paradigm may also help to characterize the heterogeneity of the glioma TME with respect to the degree of myeloid cell infiltration at various disease stages. [18F]DPA-714 may also facilitate the development of new image-guided therapies targeting the myeloid-derived TME.

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Zhang, Wei, Liu Li, Piao-Piao Bian, Qiu-Ping Luo y Zhong-Tang Xiong. "PLEKHA4 Is a Prognostic Biomarker and Correlated with Immune Infiltrates in Glioma". BioMed Research International 2023 (17 de enero de 2023): 1–21. http://dx.doi.org/10.1155/2023/4504474.

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Objective. Gliomas are the most common and life-threatening intracranial tumors. Immune infiltration of the tumor microenvironment significantly affects tumor prognosis in glioma. Recently, PLEKHA4 was reported to be upregulated in melanoma and closely associated with tumor genesis and development, but its role in glioma is poorly understood. Our aim was to investigate the expression, functional role, and prognostic value of PLEKHA4 in glioma. Methods. The expression levels of PLEKHA4 in 33 types of cancer in the TCGA (The Cancer Genome Atlas) database were collected via the UCSC Xena browser. The clinical samples of glioma patients were downloaded from the TCGA database. Immunohistochemistry was used to verify PLEKHA4 expression in tumor tissues. We assessed the influence of PLEKHA4 on survival of glioma patients by survival module and GEPIA. Then, we downloaded datasets of glioma from TCGA and investigated the correlations between the clinical characteristics and PLEKHA4 expression using logistic regression. Moreover, we used TIMER to explore the collection of PLEKHA4 expression and immune infiltration level in glioma and to analyze cumulative survival in glioma. Gene Set Enrichment Analysis (GSEA) was performed using the TCGA dataset. Results. PLEKHA4 transcript levels were significantly upregulated in multiple cancer types, including gliomas. Moreover, immunohistochemical analysis verified that PLEKHA4 was overexpressed in gliomas compare to the corresponding normal tissues. Univariable survival and multivariate cox analysis show that increased PLEKHA4 expression significantly correlated with age, tumor grade, IDH mutation status, and 1p/19q codel status, and higher PLEKHA4 had shorter OS, DSS, and PFI. Specifically, PLEKHA4 expression level had significant positive correlations with infiltrating levels of B cell, CD4+ T cells, CD8+ T cells, macrophages, neutrophils, and DCs in glioma, and upregulation of PLEKHA4 expression was significantly related to immune cell biomarkers and immune checkpoint expression in glioma. In addition, several GO and Kyoto Encyclopedia of Genes and Genomes (KEGG) items associated with immune response, JAK STAT signal pathway, and cell cycle were significantly enriched in the high PLEKHA4 expression phenotype pathway. Conclusions. Our findings proposed that PLEKHA4 was an independent prognostic biomarker and correlated with immune infiltrates in glioma, and targeting PLEKHA4 might improve immunotherapy in glioma. Of course, these findings also need basic experiments and further clinical trials to confirm in the future.

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D'Angelo, Fulvio, Luciano Garofano, Young Taek Oh, Ryan Najac, Michele Ceccarelli, Marica Eoli, Marc Sanson, Anna Lasorella y Antonio Iavarone. "EPCO-27. REVEALING TUMOR HETEROGENEITY AND IMMUNE MICROENVIRONMENT IN NF-1 GLIOMA BY SINGLE-CELL GENE EXPRESSION PROFILING". Neuro-Oncology 24, Supplement_7 (1 de noviembre de 2022): vii121—vii122. http://dx.doi.org/10.1093/neuonc/noac209.461.

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Abstract Germline mutations in the NF1 tumor suppressor gene cause neurofibromatosis type 1 (NF-1), the most common human genetic cancer predisposition syndrome. NF1 patients are prone to develop peripheral and central nervous system tumors, with glioma occurring in 15-20% of patients. The molecular profiles of glioma from patients with NF-1 have been previously explored by large scale DNA and RNA bulk analyses, providing the first comprehensive genetic landscape of NF-1 glioma. However, the intra-tumoral architecture and the microenvironment organization remained largely concealed within the global bulk profile. Here, to characterize the complexity of molecular states of both malignant and non-malignant cells, we profiled NF-1 glioma gene expression at individual cell resolution. We performed single-nuclei RNA sequencing (Nucseq) on frozen NF-1 glioma specimens, including high-grade and low-grade tumors. The functional classification of the transcriptional programs activated in the individual tumor cells identified three main molecular states that partially overlapped with the cellular subtypes of sporadic glioblastoma. Tumor cells of low-grade NF-1 glioma exhibited marked enrichment of neuronal functions, suggesting that the gliomagenesis process in the context of NF1 inactivation might be supported by specialized neuronal activities. Conversely, the proliferative state characterized high-grade NF-1 glioma, indicating that cell cycle-associated pathways are drivers of tumor progression. The single-cell deconvolution of immune microenvironment in NF-1 low grade glioma revealed infiltration of CD8+ T lymphocytes and the active crosstalk of these cells with pro-inflammatory macrophages and mature dendritic cells, supporting a possible anti-tumor cell-mediated response. The identification of divergent tumor cell states as well as the characterization of the immune infiltrates provide new insights for accurate stratification of NF-1 glioma patients and to inform personalized therapeutics.

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Lee, Sungho, Khatri Latha y Ganesh Rao. "TMIC-61. ROLE OF CX3CR1 SIGNALING IN MALIGNANT TRANSFORMATION OF GLIOMAS". Neuro-Oncology 21, Supplement_6 (noviembre de 2019): vi261. http://dx.doi.org/10.1093/neuonc/noz175.1095.

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Abstract High-grade gliomas (HGGs), including the most common primary brain tumor, glioblastoma (GBM), may arise from malignant transformation of low-grade gliomas (LGGs). While LGGs are often clinically indolent, GBMs have dismal outcomes despite maximal therapy. Accumulating data suggest that chemokine signaling directly contributes to malignant transformation of LGGs by altering tumor behavior or impacting the immune microenvironment. Here, we examined the role of CX3CR1 signaling in the malignant transformation of LGGs. First, patients with malignantly transformed LGGs were genotyped for the presence of the common loss-of-function CX3CR1 V249I polymorphism, and median overall survival was compared between the genotypes. Second, RNA sequencing data was analyzed for differential gene expression based on genotype. Third, surgical samples were examined for altered expression of M2 macrophage markers and microvessel density between the genotypes. Finally, a genetically-engineered murine model was leveraged to model endogenous intracranial gliomas with targeted expression of CX3CL1 and CX3CR1, individually or in combination. Our data demonstrate that heterozygosity (V/I) or homozygosity (I/I) for the loss-of-function CX3CR1 polymorphism was associated with significantly better median overall survival in patients with LGGs that have transformed to HGGs, compared to the wild type genotype (V/V). In addition, HGGs from V/I and I/I genotypes exhibit significantly decreased levels of CCL2, important for the recruitment of M2 macrophages, as well as decreased levels of ANGPT1 and MMP9, which mediate angiogenesis. This correlates with reduced intratumoral accumulation of CD204 positive macrophages and microvessel density in tumors from V/I and I/I patients. Finally, in the RCAS-PDGFB driven model of LGG, co-expression of CX3CL1 and CX3CR1 promotes more malignant tumor phenotype and shorter tumor-free survival. Taken together, our results show that CX3CR1 signaling promotes malignant transformation of LGGs via accumulation of glioma associated M2 macrophages and microglia and increased angiogenesis.

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Abdelfattah, Nourhan, Parveen Kumar, Caiyi Wang, Jia-Shiun Leu, William W. Flynn, Ruli Gao, David S. Baskin et al. "Abstract 2540: A multi-dimensional analysis of human gliomas at the single cell level identifies immune suppressive macrophage molecular signatures and a novel immunotherapy target for GBM". Cancer Research 82, n.º 12_Supplement (15 de junio de 2022): 2540. http://dx.doi.org/10.1158/1538-7445.am2022-2540.

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Abstract Glioblastoma (GBM) is the most prevalent primary brain malignancy in adults. The current standard of care includes maximal surgical resection followed by radio- and chemotherapy with temozolomide. Yet <5% of GBM patients survive more than five years. This indicates a desperate need for more effective treatments, such as immunotherapy for GBM patients. Unfortunately, most immunotherapy trials, including vaccines, adoptive cellular therapy, CAR-T cells, and checkpoint blockade, showed only modest benefits in GBM patients. A major barrier to immunotherapy efficacy is GBM’s immunosuppressive microenvironment composed of few tumor infiltrating lymphocytes (TILs; <5%) but abundant myeloid cells, making it an immune cold tumor. By contrast, immune hot tumors, characterized by abundant tumoricidal effector T cells necessary to mount a meaningful attack, have consistently responded better to immunotherapy. Hence, a better definition of the heterogeneous cell types in the GBM microenvironment and their function is urgently needed. Fortunately, single cell transcriptomics approaches provide comprehensive and high-resolution cellular and molecular understanding to resolve this heterogeneity. Here we report an integrated, multiregional and -dimensional single cell transcriptomic analysis of 201,986 human glioma and immune cells derived from 44 tissue fragments from 18 human glioma patients. In doing so, we map GBM cellular heterotypia and spatial, molecular, and functional heterogeneity of glioma associated immune cells. We report extensive spatial and molecular heterogeneity of glioma cells, microglia, macrophages, and T cells within the same tumor samples in low grade gliomas, primary GBMs, and recurrent GBMs. Importantly, our analysis of 83,479 glioma infiltrating myeloid cells identifies 9 molecularly distinct myeloid subtypes: 4 microglial, 4 bone marrow derived macrophage and dendritic cells subtypes. Importantly, in multiple independent glioma patient cohorts, 5 of these myeloid cell subtype gene signatures were independent predictors of patient survival. We also provide evidence that cell:cell communication between glioma and immune cells is more robust than glioma:Tcells, indicating that myeloid cells form a communication hub in vivo. Additionally, we identified S100A4 as highly expressed in immunosuppressive macrophages and T cells, and provide in vitro and in vivo evidence that S100a4 plays a critical role in promoting immunosuppressive phenotypes in glioma associated leukocytes. This study not only provides the first comprehensive single cell atlas of GBM to include both glioma and immune cells from same samples but also demonstrates its utility in elucidating cell:cell communication among different cell types in vivo and discovering new therapeutic targets for this poorly immunogenic cancer. Citation Format: Nourhan Abdelfattah, Parveen Kumar, Caiyi Wang, Jia-Shiun Leu, William W. Flynn, Ruli Gao, David S. Baskin, Kumar Pichumani, Omkar B. Ijare, Stephanie Wood, Suzanne Powell, David Haviland, Frederick F. Lang, Sujit Prabhu, Kristin Huntoon, Brittany C. Parker Kerrigan, Wen Jiang Jiang, Betty Y. Kim, Joshy George, Kyuson Yun. A multi-dimensional analysis of human gliomas at the single cell level identifies immune suppressive macrophage molecular signatures and a novel immunotherapy target for GBM [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2540.

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Nabiul Hasan, Md, Xiudong Guan, Avani Ahuja, Maria Castro, Gary Kohanbash y Dandan Sun. "TMIC-19. H+ EXTRUSION PROTEIN NA/H EXCHANGER IN METABOLIC POLARIZATION OF GLIOMA-ASSOCIATED MICROGLIA/MACROPHAGES AND TUMOR IMMUNITY". Neuro-Oncology 21, Supplement_6 (noviembre de 2019): vi251. http://dx.doi.org/10.1093/neuonc/noz175.1053.

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Abstract Immunosuppressive tumor microenvironment (TME) in glioblastoma (GBM) attributes to poor efficacy of chemotherapy and/or immunotherapy. We recently reported that SLC9A1 gene expression (Na/H exchanger 1, NHE1) in GBM tumor correlates with increased macrophage tumor infiltration and worsened patient survival. Temozolomide (TMZ) monotherapy, the standard care therapy for GBM, stimulates NHE1 protein expression in mouse syngeneic glioma models. We speculate that in response to TMZ therapy, NHE1 promotes immunosuppressive TME development via deregulation of glucose metabolism and anti-tumor function of immune cells. CD57BL/6 mice bearing GL26 glioma tumor were treated with NHE1 inhibitor HOE-642 (H, 0.3 mg/kg/day), TMZ (T, 2.5 mg/kg/day), and/or anti-PD-1 (10 mg/kg/day) monotherapy or in combination. The T+H+anti-PD-1 combination therapy increased glucose uptake (2-NBDG) and mitochondrial mass (mitotracker fluorescent intensity) of tumor infiltrating CD8+ T-cells by ~2-fold compared to the monotherapies. This suggests that NHE1 protein is involved in metabolic transformation of T-cells and affects their responses to chemo and/or immunotherapy. Furthermore, we detected that specific deletion of Nhe1 in Cx3Cr1CreErT2r+/-;Nhe1f/f mice (Nhe1 KO) alters activation of glioma-associated microglia/macrophages (GAM) and T-cells in response to TMZ therapy. TMZ monotherapy stimulated macrophage (CD11b+CD45hi) infiltration by ~2.5-fold in Cx3Cr1CreErT2-/-;Nhe1f/f (Nhe1 Con) mice bearing SB28-GFP glioma tumor with abundant proinflammatory CD16/32+ GAMs. In contrast, TMZ treated Nhe1 KO mice displayed ~3-fold reduction in tumor infiltrating GAMs with nearly abolished Ym-1+ tolerogenic macrophages, ~3-fold reduction of tumor-promoting CD4+CD25+FoxP3+ regulatory T-cells (Treg) and increased CD8+/Treg ratio by ~2-fold than the Nhe1 Con mice. Importantly, TMZ followed by anti-PD-1 therapy prolonged survival of Nhe1 KO mice but not Nhe1 Con mice. Taken together, our study suggests that NHE1 is involved in transformation of GAMs and PD-1 check point activation of T-cells. Blocking NHE1 function in combination with TMZ and anti-PD-1 may restore glucose metabolism of immune cells necessary for their anti-tumor function.

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Bianconi, Andrea, Gelsomina Aruta, Francesca Rizzo, Luca Francesco Salvati, Pietro Zeppa, Diego Garbossa y Fabio Cofano. "Systematic Review on Tumor Microenvironment in Glial Neoplasm: From Understanding Pathogenesis to Future Therapeutic Perspectives". International Journal of Molecular Sciences 23, n.º 8 (9 de abril de 2022): 4166. http://dx.doi.org/10.3390/ijms23084166.

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Despite the multidisciplinary management in the treatment of glioblastomas, the average survival of GBM patients is still 15 months. In recent years, molecular biomarkers have gained more and more importance both in the diagnosis and therapy of glial tumors. At the same time, it has become clear that non neoplastic cells, which constitute about 30% of glioma mass, dramatically influence tumor growth, spread, and recurrence. This is the main reason why, in recent years, scientific research has been focused on understanding the function and the composition of tumor microenvironment and its role in gliomagenesis and recurrence. The aim of this review is to summarize the most recent discovery about resident microglia, tumor-associated macrophages, lymphocytes, and the role of extracellular vesicles and their bijective interaction with glioma cells. Moreover, we reported the most recent updates about new therapeutic strategies targeting immune system receptors and soluble factors. Understanding how glioma cells interact with non-neoplastic cells in tumor microenvironment is an essential step to comprehend mechanisms at the base of disease progression and to find new therapeutic strategies for GBM patients. However, no significant results have yet been obtained in studies targeting single molecules/pathways; considering the complex microenvironment, it is likely that only by using multiple therapeutic agents acting on multiple molecular targets can significant results be achieved.

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Xu, Can, Menglin Xiao, Xiang Li, Lei Xin, Jia Song, Qi Zhan, Changsheng Wang et al. "Origin, activation, and targeted therapy of glioma-associated macrophages". Frontiers in Immunology 13 (6 de octubre de 2022). http://dx.doi.org/10.3389/fimmu.2022.974996.

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The glioma tumor microenvironment plays a crucial role in the development, occurrence, and treatment of gliomas. Glioma-associated macrophages (GAMs) are the most widely infiltrated immune cells in the tumor microenvironment (TME) and one of the major cell populations that exert immune functions. GAMs typically originate from two cell types-brain-resident microglia (BRM) and bone marrow-derived monocytes (BMDM), depending on a variety of cytokines for recruitment and activation. GAMs mainly contain two functionally and morphologically distinct activation types- classically activated M1 macrophages (antitumor/immunostimulatory) and alternatively activated M2 macrophages (protumor/immunosuppressive). GAMs have been shown to affect multiple biological functions of gliomas, including promoting tumor growth and invasion, angiogenesis, energy metabolism, and treatment resistance. Both M1 and M2 macrophages are highly plastic and can polarize or interconvert under various malignant conditions. As the relationship between GAMs and gliomas has become more apparent, GAMs have long been one of the promising targets for glioma therapy, and many studies have demonstrated the therapeutic potential of this target. Here, we review the origin and activation of GAMs in gliomas, how they regulate tumor development and response to therapies, and current glioma therapeutic strategies targeting GAMs.

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Zhou, Fengqi, Qinyu Shi, Xiao Fan, Ruilei Yu, Zhiqiang Wu, Binbin Wang, Wei Tian et al. "Diverse Macrophages Constituted the Glioma Microenvironment and Influenced by PTEN Status". Frontiers in Immunology 13 (21 de febrero de 2022). http://dx.doi.org/10.3389/fimmu.2022.841404.

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The glioma immune microenvironment (GIM), consisting of glioma cells, stromal cells, and immune cells, accelerates the initiation, development, immune evasion, chemoresistance, and radioresistance of glioblastoma (GBM), whereas the immunosuppressive mechanisms of GBM have not been thoroughly elucidated to date. The glioma data downloaded from The Cancer Genome Atlas (TCGA) and the Chinese Glioma Genome Atlas (CGGA) databases were used to evaluate the composition of tumor-infiltrating immune cells (TICs) by the CIBERSORT algorithm. RNA-seq datasets from the TCGA and CGGA were used to analyze the relationship between immune scores with patients’ characteristics and TICs, which showed higher ratios of tumor-inhibiting/tumor-promoting signatures (M2/M1 macrophages) along with higher immune scores. The distribution of TICs among different glioma patients and the correlation with hazard ratio (HR) analysis suggested that M2 macrophages were abundant in malignant gliomas and indicated an unfavorable prognosis. We further analyzed TCGA cases with available mutation and copy-number alteration information, which showed that the status of PTEN could influence the immune microenvironment of glioma patients. Tissue microarrays of 39 GBM patients were carried out to confirm the clinical significance of PTEN and macrophage markers. We found that the high expression of PTEN was associated with a more extended survival period of glioma patients, positively correlated with M2 macrophages and negatively with M1 macrophages. Transwell and flow cytometry analyses demonstrated that PTEN status could prevent M1 to M2 polarization and M2 macrophage recruitment of gliomas in vitro. The newly discovered immunoregulatory activity of PTEN opens innovative avenues for investigations relevant to counteracting cancer development and progression.

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Cai, Xiangming, Feng Yuan, Junhao Zhu, Jin Yang, Chao Tang, Zixiang Cong y Chiyuan Ma. "Glioma-Associated Stromal Cells Stimulate Glioma Malignancy by Regulating the Tumor Immune Microenvironment". Frontiers in Oncology 11 (29 de abril de 2021). http://dx.doi.org/10.3389/fonc.2021.672928.

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BackgroundThe glioma-associated stromal cell (GASC) is a recently identified type of cell in the glioma microenvironment and may be a prognostic marker for glioma. However, the potential mechanisms of GASCs in the glioma microenvironment remain largely unknown. In this work, we aimed to explore the mechanisms of GASCs in gliomas, particularly in high-grade gliomas (HGG).MethodsWe used glioma datasets from The Cancer Genome Atlas (TCGA) and the Chinese Glioma Genome Atlas (CGGA). We utilized the Single-sample Gene Set Enrichment Analysis (ssGSEA) algorithm to discriminate between patients with high or low GASC composition. The xCELL and CIBERSORT algorithms were used to analyze the composition of stromal cells and immune cells. Risk score and a nomogram model were constructed for prognostic prediction of glioma.ResultsWe observed for the first time that the levels of M2 macrophages and immune checkpoints (PD-1, PD-L1, PD-L2, TIM3, Galectin-9, CTLA-4, CD80, CD86, CD155, and CIITA) were significantly higher in the high GASC group and showed positive correlation with the GASC score in all glioma population and the HGG population. Copy number variations of DR3 and CIITA were higher in the high-GASC group. THY1, one of the GASC markers, exhibited lower methylation in the high GASC group. The constructed risk score was an independent predictor of glioma prognostics. Finally, a credible nomogram based on the risk score was established.ConclusionsGASCs stimulate glioma malignancy through the M2 macrophage, and are associated with the level of immune checkpoints in the glioma microenvironment. The methylation of THY1 could be used as prognostic indicator and treatment target for glioma. However, further studies are required to verify these findings.

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