Cellular and Molecular Identity of Tumor-Associated Macrophages in Glioblastoma

Chen, Zhihong; Feng, Xi; Herting, Cameron J.; Álvarez‐García, Virginia; Nie, Kai; Pong, Winnie W.; Rasmussen, Rikke; Dwivedi, Bhakti; Seby, Sandra; Wolf, Susanne; Gutmann, David H.; Hambardzumyan, Dolores

doi:10.1158/0008-5472.can-16-2310

Cited by 467 publications

(444 citation statements)

References 44 publications

(65 reference statements)

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“…TAMs represent a large component of GB and actively migrate to the tumor in response to tumor-secreted chemoattractants such as CSF-1, MCP-1, and GDNF (Broekman et al, 2018;Hambardzumyan et al, 2016). The majority of CD45 + cells in control and HuR KO mouse tumors were CD45 hi consistent with being tissue Mϕ and characteristic for GB (Chen et al, 2017). In KO mice, HuR was absent from IBA1+ cells within the glioma tumor ( Figure 3) and diminished peripherally in Mϕ ( Figure S2) indicating that both PMG and Mϕ express Cre recombinase.…”

Section: Discussionmentioning

confidence: 94%

Deletion of the RNA regulator HuR in tumor‐associated microglia and macrophages stimulates anti‐tumor immunity and attenuates glioma growth

Wang

Leavenworth

Hjelmeland

et al. 2019

Glia

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Glioblastoma is a malignant brain tumor that portends a poor prognosis. Its resilience, in part, is related to a remarkable capacity for manipulating the microenvironment to promote its growth and survival. Microglia/macrophages are prime targets, being drawn into the tumor and stimulated to produce factors that support tumor growth and evasion from the immune system. Here we show that the RNA regulator, HuR, plays a key role in the tumor‐promoting response of microglia/macrophages. Knockout (KO) of HuR led to reduced tumor growth and proliferation associated with prolonged survival in a murine model of glioblastoma. Analysis of tumor composition by flow cytometry showed that tumor‐associated macrophages (TAMs) were decreased, more polarized toward an M1‐like phenotype, and had reduced PD‐L1 expression. There was an overall increase in infiltrating CD4+ cells, including Th1 and cytotoxic effector cells, and a concomitant reduction in tumor‐associated polymorphonuclear myeloid‐derived suppressor cells. Molecular and cellular analyses of HuR KO TAMs and cultured microglia showed changes in migration, chemoattraction, and chemokine/cytokine profiles that provide potential mechanisms for the altered tumor microenvironment and reduced tumor growth in HuR KO mice. In summary, HuR is a key modulator of pro‐glioma responses by microglia/macrophages through the molecular regulation of chemokines, cytokines, and other factors. Our findings underscore the relevance of HuR as a therapeutic target in glioblastoma.

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Section: Discussionmentioning

confidence: 94%

Deletion of the RNA regulator HuR in tumor‐associated microglia and macrophages stimulates anti‐tumor immunity and attenuates glioma growth

Wang

Leavenworth

Hjelmeland

et al. 2019

Glia

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“…To elucidate the clinical and genetic features of lymphocyte and neutrophil type gliomas, we clustered glioma samples from CGGA and TCGA dataset by k ‐means ( k = 2) method. Tumor‐associated macrophage (TAM), playing crucial roles in glioma progression, represent about more than a half of immune cells in tumor mass . Here, we used transcriptome data to generate enrichment score with macrophage signatures and depicted the characteristics of macrophage in lymphocyte and neutrophil type gliomas.…”

Section: Resultsmentioning

confidence: 99%

“…Tumor-associated macrophage (TAM), playing crucial roles in glioma progression, represent about more than a half of immune cells in tumor mass. 19,20 Here, we used transcriptome data to generate enrichment score with mac- Higher macrophage enrichment scores were more likely to belong to neutrophil subtype glioma. Lymphocyte type glioma patients (median survival not reached, median follow-up 1047 days) had significant longer survival than neutrophil ones (median survival 386 days, P < 0.0001, Figure 4B).…”

Section: Clinicopathological Features Of Lymphocyte and Neutrophilmentioning

confidence: 99%

Peripheral blood test provides a practical method for glioma evaluation and prognosis prediction

et al. 2019

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Summary Objective To investigate the relationship between tumor characteristics and the preoperative counts of immune cells in peripheral blood test in glioma patients. Methods We included 260 WHO grades II‐IV patients who had preoperative peripheral blood test result from Sanbo hospital as training set. The 66 patients from Tiantan hospital was obtained for validation. RNA sequencing data from CGGA and TCGA datasets were used to evaluate the features of neutrophil subtype and lymphocyte subtype in glioma. Results We revealed that the count of preoperative lymphocytes, eosinophils and neutrophils were associated with glioma grades. Neutrophil‐to‐lymphocyte ratio (NLR) <3.2 was associated with better prognosis, whereas increased NLR was strongly corresponding with a poor prognosis. Lymphocyte type glioma patients demonstrated a positive correlation with isocitrate dehydrogenase (IDH) mutation and lower grade. IDH mutant glioma contained a higher proportion of tumor‐infiltrating lymphocytes than IDH wild‐type glioma. The immune subtype (neutrophil subtype and lymphocyte subtype) was an independent prognostic factor in glioma. Conclusion Our data demonstrated that NLR was an important prognostic factor in glioma. We classified that the immune subtype of glioma may contribute to a better understanding of disease pathogenesis and lead to the identification of new therapeutic targets for glioma patients.

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“…Non‐neoplastic cell types that form the tumor microenvironment include various infiltrating and resident immune cells, the vasculature, and other glial cell types (Hambardzumyan & Bergers, ). The most abundant non‐neoplastic population, which can be up to 30% of tumor mass, is tumor associated‐macrophages (TAMs), which are comprised of both resident brain microglia and bone marrow‐derived macrophages (Chen et al, ; Hambardzumyan & Bergers, ; Hambardzumyan, Gutmann, & Kettenmann, ). To assess this population, we used IHC for Iba1, which labels TAMs independent of their origin.…”

Section: Resultsmentioning

confidence: 99%

Genetic driver mutations define the expression signature and microenvironmental composition of high‐grade gliomas

Herting

Chen

Pitter

et al. 2017

Glia

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High-grade gliomas (HGG), including glioblastomas, are characterized by invasive growth, resistance to therapy, and high inter- and intra-tumoral heterogeneity. The key histological hallmarks of glioblastoma are pseudopalisading necrosis and microvascular proliferation, which allow pathologists to distinguish glioblastoma from lower-grade gliomas. In addition to being genetically and molecularly heterogeneous, HGG are also heterogeneous with respect to the composition of their microenvironment. The question of whether this microenvironmental heterogeneity is driven by the molecular identity of the tumor remains controversial. However, this question is of utmost importance since microenvironmental, non-neoplastic cells are key components of the most radiotherapy- and chemotherapy-resistant niches of the tumor. Our work demonstrates a versatile, reliable, and reproducible adult HGG mouse model with NF1-silencing as a driver mutation. This model shows significant differences in tumor microenvironment, expression of subtype-specific markers, and response to standard therapy when compared to our established PDGFB-overexpressing HGG mouse model. PDGFB-overexpressing and NF1-silenced murine tumors closely cluster with human proneural and mesenchymal subtypes, as well as PDGFRA-amplified and NF1-deleted/mutant human tumors, respectively, at both the RNA and protein expression levels. These models can be generated in fully immunocompetent mixed or C57BL/6 genetic background mice, and therefore can easily be incorporated into preclinical studies for cancer cell-specific or immune cell-targeting drug discovery studies.

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Cellular and Molecular Identity of Tumor-Associated Macrophages in Glioblastoma

Cited by 467 publications

References 44 publications

Deletion of the RNA regulator HuR in tumor‐associated microglia and macrophages stimulates anti‐tumor immunity and attenuates glioma growth

Deletion of the RNA regulator HuR in tumor‐associated microglia and macrophages stimulates anti‐tumor immunity and attenuates glioma growth

Peripheral blood test provides a practical method for glioma evaluation and prognosis prediction

Genetic driver mutations define the expression signature and microenvironmental composition of high‐grade gliomas

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