Macrophages and microglia in glioblastoma: heterogeneity, plasticity, and therapy

Khan, Fatima; Pang, Lizhi; Dunterman, Madeline; Lesniak, Maciej S.; Heimberger, Amy B.; Chen, Peiwen

doi:10.1172/jci163446

Cited by 145 publications

(100 citation statements)

References 114 publications

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“…2D). Collectively, these results suggest that lysosomes/endolysosomes are prominent cellular components of GBM tumor-associated macrophages (TAMs), a major, heterogeneous population of cells that are key to shaping immune microenvironment and mediating immunosuppression in GBM [18][19][20] .…”

Section: Resultsmentioning

confidence: 99%

“…In-depth examination of the MC3 genes further corroborates the roles of endolysosomes in GBM pathogenesis and, specifically, in immunosuppression. First, we assessed the relationship between the 21 MC3 genes and a set of four genes representative of GBM’s immune suppressive microenvironment: the immunosuppressive TAM markers MRC1 (CD206) and CD163 18 and the immunosuppressive cytokines IL10 and TGFB1 18,20 , and found overwhelmingly positive correlations between these two groups of genes ( Fig. 4A-B, Supplementary Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Findings presented in this study also inform our understanding of TAMs and have direct implications for targeting the endolysosomal system for cancer treatments in several ways. First, while the heterogeneity and plasticity of TAMs, as defined by their distinct gene expression profiles / featured molecular pathways (e.g., Hallmark pathways), have been well documented in GBMs, they can also be viewed in a highly simplified way as two functionally opposite types (i.e., immunosuppressive/pro-tumorigenic and immunoactive/anti-tumorigenic) that produce different cytokines and/or respond to cytokines in different ways 18,21 . Our cellular component-focused findings suggest that heterogenous and functionally opposite TAMs also depend on distinct cellular organelles for exerting their pro- or anti-tumorigenic effects.…”

Section: Discussionmentioning

confidence: 99%

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Gene expression analysis suggests immunosuppressive roles of endolysosomes in glioblastoma

Sun,

Yao,

Yang

et al. 2023

Preprint

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Targeting endolysosomes is a strategy extensively pursued for treating cancers, including glioblastomas (GBMs), mainly on the basis that the intact function of these subcellular organelles is key to tumor cell autophagy and survival. Here, by gene expression analyses and cell type abundance estimation in GBMs, we showed that genes associated with the endolysosomal machinery are more prominently featured in non-tumor cells in GBMs than in tumor cells, and that tumor-associated macrophages represent the primary immune cell type that contributes to this trend. Further analyses found an enrichment of endolysosomal pathway genes in immunosuppressive (pro-tumorigenic) macrophages, such as M2-like macrophages or those associated with worse prognosis in glioma patients, but not in those linked to inflammation (anti-tumorigenic). Specifically, genes critical to the hydrolysis function of endolysosomes, including progranulin and cathepsins, were among the most positively correlated with immunosuppressive macrophages, and elevated expression of these genes is associated with worse patient survival in GBMs. Together, these results implicate the hydrolysis function of endolysosomes in shaping the immunosuppressive microenvironment of GBM. We propose that targeting endolysosomes, in addition to its detrimental effects on tumor cells, can be leveraged for modulating immunosuppression to render GBMs more amendable to immunotherapies.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Gene expression analysis suggests immunosuppressive roles of endolysosomes in glioblastoma

Sun,

Yao,

Yang

et al. 2023

Preprint

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“…The brain TME includes endothelial cells, pericytes, astrocytes, neurons, oligodendrocytes and immune cells. Although GBMs are known as 'cold tumors' with very little lymphocytic infiltration 3 , the GBM TME contains up to 40% of myeloid cells, which, as a whole, are referred to as tumorassociated macrophages (TAMs) and are known to create a supportive environment facilitating tumor proliferation, survival and migration 4,5 . TAMs are mainly constituted by brain resident parenchymal microglia (Mg), peripheral monocytes (Mo) and perivascular macrophages, known as border-associated macrophages (BAMs) [6][7][8] .…”

Section: Introductionmentioning

confidence: 99%

Glioblastoma-instructed microglia transition to heterogeneous phenotypic states with phagocytic and dendritic cell-like features in patient tumors and patient-derived orthotopic xenografts

Yabo

Moreno-Sanchez

Pires‐Afonso

et al. 2023

Preprint

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BackgroundGlioblastoma (GBM) evades the immune system by creating an immune-suppressive tumor microenvironment (TME), where GBM-associated myeloid cells are geared towards tumor-supportive roles. However, it is unclear whether recruited myeloid cells are phenotypically and functionally identical. Here, we aim to understand the TME heterogeneity in GBM patients recapitulated in patient-derived orthotopic xenografts (PDOXs) and systematically characterize myeloid cell type identities at the molecular and functional level.MethodsWe applied single-cell RNA-sequencing and spatial transcriptomics, multicolor flow cytometry, immunohistochemistry and functional assays to examine the heterogeneity of the TME in GBM. Various GBM PDOXs representing different tumor phenotypes were analyzed and compared to the patient tumors, normal brain and mouse GL261 glioma model.ResultsPDOX models recapitulate the major components of the TME detected in human GBM, where tumor cells reciprocally interact with host cells to create a GBM-specific TME. We detect the most prominent transcriptomic adaptations in myeloid cells, which are largely of microglial origin. We reveal intra-tumoral heterogeneity of microglia and identify diverse phenotypic states across distinct GBM landscapes and tumor niches. GBM-educated microglia acquire dendritic cell-like features, displaying increased migration and phagocytosis. We further find novel microglial states expressing astrocytic and endothelial markers. Lastly, we show that temozolomide (TMZ) treatment leads to transcriptomic plasticity of both GBM tumor cells and adjacent TME components.ConclusionsOur data provide insight into the phenotypic adaptation of the heterogeneous TME instructed by GBM. We uncover that GBM-educated microglia are represented by various concomitant states, both in patients and recapitulated in PDOXs, displaying different pro- or anti-tumoral properties that are modulated by anti-neoplastic treatments, such as TMZ.KEY POINTSGBM-educated tumor microenvironment is faithfully recapitulated and modulated in PDOX modelsMicroglia represent an essential myeloid cell population in the GBM microenvironmentGBM-educated microglia acquire heterogeneous transcriptomic states across distinct tumor nichesGBM-educated microglia subsets display phagocytic and dendritic cell-like gene expression programs, which are modulated upon TMZ treatmentIMPORTANCE OF THE STUDYThis manuscript addresses tumor-immune interactions in GBM, focusing on the molecular changes of the myeloid compartment. We find that myeloid cells, the most abundant immune cell population in brain tumors, undergo the most prominent transcriptional adaptation in the TME. Resident microglia represent the main myeloid cell population in the cellular tumor, while peripheral-derived myeloid cells appear to infiltrate the brain at sites of blood-brain barrier disruption. We identify reactive dendritic cell-like gene expression programs associated with enhanced phagocytic and antigen-presentation features in GBM-educated microglia subsets that might be harnessed for novel immunotherapeutic approaches. Overall, PDOX models faithfully recapitulate the major components of the GBM-educated TME and allow assessment of phenotypic changes in the GBM ecosystem upon treatment.

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“…In addition, high lactate levels produced by the Warburg effect have been demonstrated as a key immunosuppressive metabolite in the tumor microenvironment (TME). 18 Research has shown that the Warburg effect leads to the formation of an immunosuppressive microenvironment by maintaining a low potential hydrogen value in the TME, 18,19 such as by polarizing tumor-associated macrophages to favor the M2 phenotype, 20,21 promoting the depletion of cytotoxic T cells, 22 and thereby promoting tumor progression. However, the role of the Warburg effect on other cells involved in tumor immunity has not been clearly reported, especially the role of the Warburg effect on the immune cell profile in the GBM immune microenvironment.…”

Section: Introductionmentioning

confidence: 99%

Warburg effect‐related risk scoring model to assess clinical significance and immunity characteristics of glioblastoma

Zhang,

Wang,

Zheng

et al. 2023

Cancer Medicine

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BackgroundGlioblastoma (GBM), the most common primary malignant brain tumor, has a poor prognosis, with a median survival of only 14.6 months. The Warburg effect is an abnormal energy metabolism, which is the main cause of the acidic tumor microenvironment. This study explored the role of the Warburg effect in the prognosis and immune microenvironment of GBM.MethodsA prognostic risk score model of Warburg effect‐related genes (Warburg effect signature) was constructed using GBM cohort data from The Cancer Genome Atlas. Cox analysis was performed to identify independent prognostic factors. Next, the nomogram was built to predict the prognosis for GBM patients. Finally, the drug sensitivity analysis was utilized to find the drugs that specifically target Warburg effect‐related genes.ResultsAge, radiotherapy, chemotherapy, and WRGs score were confirmed as independent prognostic factors for GBM by Cox analyses. The C‐index (0.633 for the training set and 0.696 for the validation set) and area under curve (>0.7) indicated that the nomogram exhibited excellent performance. The calibration curve also indicates excellent consistency of the nomogram between predictions and actual observations. In addition, immune microenvironment analysis revealed that patients with high WRGs scores had high immunosuppressive scores, a high abundance of immunosuppressive cells, and a low response to immunotherapy. The Cell Counting Kit‐8 assays showed that the drugs targeting Warburg effect‐related genes could inhibit the GBM cells growth in vitro.ConclusionOur research showed that the Warburg effect is connected with the prognosis and immune microenvironment of GBM. Therefore, targeting Warburg effect‐related genes may provide novel therapeutic options.

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Macrophages and microglia in glioblastoma: heterogeneity, plasticity, and therapy

Cited by 145 publications

References 114 publications

Gene expression analysis suggests immunosuppressive roles of endolysosomes in glioblastoma

Gene expression analysis suggests immunosuppressive roles of endolysosomes in glioblastoma

Glioblastoma-instructed microglia transition to heterogeneous phenotypic states with phagocytic and dendritic cell-like features in patient tumors and patient-derived orthotopic xenografts

Warburg effect‐related risk scoring model to assess clinical significance and immunity characteristics of glioblastoma

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