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CSF-1R inhibition alters macrophage polarization and blocks gliomagenesis

ABSTRACT: Glioblastoma multiforme (GBM), the most common and aggressive primary brain tumor in adults, can be divided into several molecular subtypes including proneural GBM. Most clinical strategies aimed at directly targeting glioma cells in these tumors have failed. A promising alternative is to target stromal cells in the brain microenvironment, such as tumor-associated microglia and macrophages (TAMs). Macrophages are dependent upon colony stimulating factor (CSF)-1 for differentiation and survival; therefore, we used an inhibitor of its receptor, CSF-1R, to target macrophages in a mouse proneural GBM model. CSF-1R inhibition dramatically increased survival in mice and regressed established GBMs. Tumor cell apoptosis was significantly increased, and proliferation and tumor grade markedly decreased. Surprisingly, TAMs were not depleted in tumors treated with the CSF-1R inhibitor. Instead, analysis of gene expression in TAMs isolated from treated tumors revealed a decrease in alternatively activated/ M2 macrophage markers, consistent with impaired tumor-promoting functions. These gene signatures were also associated with better survival specifically in the proneural subtype of patient gliomas. Collectively, these results establish macrophages as valid therapeutic targets in proneural gliomas, and highlight the clinical potential for CSF-1R inhibitors in GBM.

ORGANISM(S): Mus musculus

PROVIDER: GSE37475 | GEO | 2013/09/20

SECONDARY ACCESSION(S): PRJNA160215

REPOSITORIES: GEO

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CSF-1R inhibition alters macrophage polarization and blocks gliomagenesis

Project description:Glioblastoma multiforme (GBM), the most common and aggressive primary brain tumor in adults, can be divided into several molecular subtypes including proneural GBM. Most clinical strategies aimed at directly targeting glioma cells in these tumors have failed. A promising alternative is to target stromal cells in the brain microenvironment, such as tumor-associated microglia and macrophages (TAMs). Macrophages are dependent upon colony stimulating factor (CSF)-1 for differentiation and survival; therefore, we used an inhibitor of its receptor, CSF-1R, to target macrophages in a mouse proneural GBM model. CSF-1R inhibition dramatically increased survival in mice and regressed established GBMs. Tumor cell apoptosis was significantly increased, and proliferation and tumor grade markedly decreased. Surprisingly, TAMs were not depleted in tumors treated with the CSF-1R inhibitor. Instead, analysis of gene expression in TAMs isolated from treated tumors revealed a decrease in alternatively activated/ M2 macrophage markers, consistent with impaired tumor-promoting functions. These gene signatures were also associated with better survival specifically in the proneural subtype of patient gliomas. Collectively, these results establish macrophages as valid therapeutic targets in proneural gliomas, and highlight the clinical potential for CSF-1R inhibitors in GBM. RNA was isolated from sorted tumor associated macrophages (TAMs) from murine gliomas following either 7 days of vehicle or BLZ945 treatment. Samples were collected from 16 total tumor burdened mice, with 8 replicates for each treatment group. BLZ945: a Colony-Stimulating Factor 1 Receptor (CSF-1R) inhibitor

2013-09-20 | E-GEOD-37475 | biostudies-arrayexpress

A paracrine IGF1/IGF1R-PI3K signaling loop underlies resistance to CSF-1R inhibition in GBM

Project description:Glioblastoma multiforme (GBM) is the most aggressive form of glioma, and is notorious for its terminal prognosis and lack of responsiveness to current treatment approaches. The brain tumor microenvironment (TME) represents a largely untapped reservoir of therapeutic target options in GBM. Here we have focused on the interplay between glioma cells and tumor-associated macrophages/ microglia (TAMs). TAMs accumulate in the gliomas with disease progression, and depend on colony stimulating factor 1 receptor (CSF-1R) signaling for survival. In a recent study from our laboratory, mice bearing high-grade gliomas were treated with a CSF-1R inhibitor, BLZ945 (Novartis), and tumors regressed significantly after just 7 days of treatment (PMID: 24056773). Here we investigate whether long-term treatment of high-grade gliomas with BLZ945 would result in stable management of disease in a mouse model of proneural GBM. We show that ~44% of mice survived to the trial end point (EP) with minimal disease by MRI and histology, whereas ~56% of mice showed tumor recurrence (Reb). Serial transplantation of rebound tumor cells into naïve animals re-established BLZ945 responsiveness, suggesting a role for the microenvironment in supporting recurrent disease. Indeed, RNA-seq analysis on FACS purified tumor cells and TAMs from EP and Reb tumors showed elevated PI3K signaling in Reb tumors, driven by a heterotypic paracrine interaction between TAM-derived IGF-1 and tumor cell IGF-1R. We performed combination trials to block IGF-1R or downstream PI3K signaling in rebound tumors with BLZ945 treatment, and were able to significantly prolong overall survival. Given that CSF-1R inhibitors are currently in clinical trials for multiple cancer types including for GBM, understanding the molecular mechanisms that underlie non-responsive/ resistant tumors is timely and critical.

2016-05-20 | GSE69104 | GEO

Microenvironment-driven IGF-1R/PI3K signaling underlies acquired resistance to CSF1R inhibition in gliomas (CGH)

Project description:Macrophages accumulate with glioblastoma multiforme (GBM) progression, and can be acutely targeted via inhibition of colony stimulating factor-1 receptor (CSF-1R) to regress high-grade tumors in animal models. However, whether and how resistance emerges in response to sustained CSF-1R blockade is unknown. Here, we investigate whether long-term CSF-1R inhibition can stably regress GBM in preclinical trials. We show that while overall survival is significantly prolonged, tumors recur eventually in >50% of mice. Upon isolation and transplantation of recurrent tumor cells into naïve animals, gliomas re-establish sensitivity to CSF-1R inhibition, indicating that resistance is microenvironment-driven. PI3K pathway activity was elevated in recurrent GBM, driven by macrophage-derived IGF-1 and tumor cell IGF-1R. Consequently, combining IGF-1R or PI3K blockade with continuous CSF-1R inhibition in recurrent tumors significantly prolonged overall survival. By contrast, monotherapy with IGF-1R or PI3K inhibitors in rebound or treatment-naïve tumors was less effective, indicating the necessity of combination therapy to expose PI3K signaling-dependency in recurrent disease. Our findings thus reveal a potential therapeutic approach for treating resistance to CSF-1R inhibitors in the clinical setting.

2016-05-20 | GSE80399 | GEO

Transcriptome sequencing analysis of CSF-1Rhigh TAMs and CSF-1Rlow TAMs in colon adenocarcinoma.

Project description:Tumor-associated macrophages (TAMs) are a major component of the leukocyte and a heterogenous population in tumors. Recent reports have increasingly suggested that manipulating the function of TAMs may serve as a promising therapeutic strategy against advanced tumors. Our present work indicates that CSF-1R+ TAMs are abundantly found in a significant proportion of COAD specimens. Therefore，to determine the role of the CSF-1Rhigh TAMs in COAD, we sorted the CSF-1Rhigh TAMs and the CSF-1R low TAMs from the colon adenocarcinomas for Smart-seq2. We found that CSF-1Rhigh TAM infiltration involved in multiple tumor immune signaling pathways. CSF-1Rhigh TAMs mostly exhibited a immunosuppressive phenotypes, and were associated with enhanced levels of Treg cells. CSF-1R high TAMs promotes COAD progression by modulating tumor immunity environment

2022-03-31 | GSE193814 | GEO

Glioblastoma Genetic Drivers Dictate the Function of Tumor-Associated Macrophages/Microglia and Responses to CSF1R Inhibition

Project description: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. 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 cellular compositions and functions in PDGFB- and RAS-driven gliomas. We found that 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 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 TAMs in mesenchymal RAS-driven GBM were enriched in pro-inflammatory and angiogenic signaling. Co-targeting of TAMs and angiogenesis decreased cell proliferation and changed the morphology of RAS-driven gliomas.Our work identify 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 characterization of the microenvironment landscape in order to optimally stratify patients for TAM-targeted therapy.

2021-10-08 | GSE185420 | GEO

CD169 is a marker of IFN-γ-stimulated inflammatory macrophages in brain tumor [CT2A]

Project description:Therapies against glioblastoma multiforme (GBM) have been largely ineffective due to the infiltration of immunosuppressive tumor-associated macrophages (TAMs). Recent studies demonstrated that TAMs can also be immune-activating. However, markers differentiating these heterogeneous macrophage populations have not been established. In this study, we identified a subset of macrophages expressing CD169 that promote an anti-tumoral microenvironment in GBM. Using single-cell transcriptome analysis, we found that CD169+ macrophages in human and mouse gliomas produced proinflammatory chemokines, leading to the accumulation of T cells and NK cells. Depletion of CD169+ macrophages shortened the survival of mice with gliomas and reduced the function of antitumor lymphocytes. We show that IFN-γ produced by NK cells was critical for the accumulation of CD169+ macrophages into gliomas. Additionally, CD169 expression on macrophages increased the phagocytosis of apoptotic glioma cells. Our finding suggests that the CD169+ subset of TAMs promotes antitumor immune responses against GBM.

2022-09-11 | GSE201553 | GEO

CD169 is a marker of IFN-γ-stimulated inflammatory macrophages in brain tumor [EGFRviii]

2022-08-24 | GSE201557 | GEO

CD169 is a marker of IFN-γ-stimulated inflammatory macrophages in brain tumor [WG vs TG]

2022-09-11 | GSE171872 | GEO

Expression data from PDGF driven mouse tumors

Project description:Background Tumor heterogeneity is a major obstacle for finding effective treatment of Glioblastoma (GBM). Based on global expression analysis, GBM can be classified into distinct subtypes: Proneural, Neural, Classical and Mesenchymal. The signatures of these different tumor subtypes may reflect the phenotypes of cells giving rise to them. However, the experimental evidence connecting any specific subtype of GBM to particular cells of origin is lacking. In addition, it is unclear how different genetic alterations interact with cells of origin in determining tumor heterogeneity. This issue cannot be addressed by studying end-stage human tumors. Methodology/Principal Findings To address this issue, we used retroviruses to deliver transforming genetic lesions to glial progenitors in adult mouse brain. We compared the resulting tumors to human GBM. We found that different initiating genetic lesions gave rise to tumors with different growth rates. However all mouse tumors closely resembled the human Proneural GBM. Comparative analysis of these mouse tumors allowed us to identify a set of genes whose expression in humans with Proneural GBM correlates with survival. Conclusions/Significance This study offers insights into the relationship between adult glial progenitors and Proneural GBM, and allows us to identify molecular alterations that lead to more aggressive tumor growth. In addition, we present a new preclinical model that can be used to test treatments directed at a specific type of GBM in future studies. Gene expression profiling was performed on 20 tumors (12 Ptenf/f and 8 Ptenf/f; p53f/f) and 3 normal brains from mice. End stage tumors were used for expression array analysis. The platform used was Affymetrix GeneChip Mouse Genome 430A 2.0 Array. The microarray labeling, hybridization and quality controls were performed by following Affymetrix protocol.

2011-05-23 | E-GEOD-29458 | biostudies-arrayexpress

Comparison of Invasive TAM sub-population to General TAM population

Project description:The tumor microenvironment modifies the malignancy of tumors. In solid tumors this environment is populated by many macrophages (tumor-associated macrophages; TAMs) that in genetic studies that depleted these cells from mouse models of breast cancer were shown to promote tumor progression to malignancy and increase metastatic potential. Mechanistic studies showed that these effects are through the stimulation of tumor cell migration, invasion, intravasation as well as an enhancement of angiogenesis. Using an in vivo invasion assay it was demonstrated that invasive carcinoma cells are a unique sub-population of tumor cells whose invasion and chemotaxis is dependent upon the co-migration of TAMs with obligate reciprocal signaling through an EGF/CSF-1 paracrine loop. In this study these invasion-promoting macrophages were isolated and subjected to analysis of their transcriptome in comparison to TAMs isolated indiscriminately to function using established macrophage markers by flow cytometry. Five biological replicates for each population (Invasive and General TAM) were used.

2010-05-16 | E-GEOD-18295 | biostudies-arrayexpress

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