Regulation of tumor associated macrophages by cooperative inflammatory signaling
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE59047 | GEO | 2015/04/28
SECONDARY ACCESSION(S): PRJNA254208
REPOSITORIES: GEO
Similar Datasets
Project description:Tumor associated macrophages show signs of both, classical pro-inflammatory as well as alternative macrophage activation. The aim of this study was to compare TAMs across tumor types, to characterize their phenotype in detail and to identify the signaling nodules involved regulating classical and alternative activation traits. To identify gene expression profiles and pathways differentially activated in tumor-associated macrophages (TAMs) we isolated TAMs from in vivo animal models of EG7 thymoma (n=3), glioma (n=3) and neuroblastoma (n=3) by tumor digestion and subsequent enrichment of CD11b+ cells using Miltenyi magnetic beads. Thymomas grown in WT or Myd88-/- mice (n=5 per group) were used to identify TLR/IL1R dependent signaling in TAMs. RNA extracted from CD11b+ TAMs was analyzed using the Affymetrx HT_MG-430_PM arrays. For in-depth analysis of the role of inflammatory signaling by TNFR1 (Tnfrsf1a) and/or Myd88, EG7 TAM populations A (CD11b+, Ly6G-, Ly6C+, MHCII-) and C (CD11b+, Ly6C-, MHCII+) were isolated by flow cytometric sorting from WT, TNFR1-/-, Myd88flox/flox; Tie2-Cre and TNFR-/-; Myd88flox/flox; Tie2-cre mice and extracted RNA was analyzed by microarray using the Mouse Gene 2.0 GeneChip arrays (n=2 per genotype and population).
2015-04-28 | E-GEOD-59047 | biostudies-arrayexpress
Project description:Activating CD8+ T cells by antigen cross-presentation is remarkably effective at eliminating tumors. Although this function is traditionally attributed to dendritic cells, tumor-associated macrophages (TAMs) can also cross-present antigens. TAMs are the most abundant tumor-infiltrating leukocyte. Yet, TAMs have not been leveraged to activate CD8+ T cells because mechanisms that modulate their ability to cross-present antigens are incompletely understood. Here we show that TAMs harbor hyperactive cysteine protease activity in their lysosomes which impedes antigen cross-presentation, thereby preventing CD8+ T cell activation. We developed a DNA nanodevice (E64-DNA) targeted to lysosomes of TAMs in mice. E64-DNA inhibits the population of cysteine proteases present specifically inside lysosomes of TAMs, improves their ability to cross-present antigens, and attenuates tumor growth via CD8+ T cells. When combined with cyclophosphamide, E64-DNA showed sustained tumor regression in a triple-negative-breast-cancer model. Our studies demonstrate that DNA nanodevices can be targeted with organelle-level precision to reprogram macrophages and achieve immunomodulation in vivo.
2021-10-14 | PXD028037 | Pride
Project description:Targeting the reprogramming and phagocytic capacities of tumor-associated macrophages (TAMs) has emerged as a therapeutic opportunity for cancer treatment. Here, we demonstrate that leukemic cell phagocytosis triggers the proinflammatory activation of TAMs as demonstrated by the upregulation and dowregulation of, respectively, proinflammatory and anti-inflammatory genes in phagocytic macrophages (Phago+) with respect to non-phagocytic macrophages (Phago-).
2022-10-25 | E-MTAB-12280 | biostudies-arrayexpress
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
Project description:Clinical and experimental evidence indicates that tumor-associated macrophages (TAMs) promote malignant progression. In breast cancer, TAMs enhance tumor angiogenesis, tumor cell invasion, matrix remodeling, and immune suppression against the tumor. In this study, we examined late-stage mammary tumors from a transgenic mouse model of breast cancer. We used flow cytometry under conditions that minimized gene expression changes to isolate a rigorously defined TAM population previously shown to be associated with invasive carcinoma cells. The gene expression signature of this population was compared with a similar population derived from spleens of non-tumor-bearing mice using high-density oligonucleotide arrays. Using stringent selection criteria, transcript abundance of 460 genes was shown to be differentially regulated between the two populations. Bioinformatic analyses of known functions of these genes indicated that formerly ascribed TAM functions, including suppression of immune activation and matrix remodeling, as well as multiple mediators of tumor angiogenesis, were elevated in TAMs. Further bioinformatic analyses confirmed that a pure and valid TAM gene expression signature in mouse tumors could be used to assess expression of TAMs in human breast cancer. The data derived from these more physiologically relevant autochthonous tumors compared with previous studies in tumor xenografts suggest tactics by which TAMs may regulate tumor angiogenesis and thus provide a basis for exploring other transcriptional mediators of TAM trophic functions within the tumor microenvironment. Tumor-associated macrophages from late-stage mouse mammary tumors compared to splenic macrophages from non-tumor-bearing littermate controls. 4 biological replicates of each population were compared via gene expression arrays.
2010-06-21 | E-GEOD-18404 | biostudies-arrayexpress
Project description:Macrophages have been implicated in breast cancer progression and metastasis, but relatively little is known about the genes and pathways that are involved. Using a conditional allele of Ets2 in the mouse, we have identified Ets2 as a critical gene in tumor associated macrophages (TAMs) that specifically promotes mammary tumor metastasis. Loss of Ets2 in TAMs decreased the frequency and size of lung metastases without impacting primary tumor burden. Expression profiling of isolated tumor macrophages established that Ets2 deficiency resulted in the de-repression of a defined set of anti-angiogenic genes. Activation of this transcriptional program correlated with decreased angiogenesis in metastatic tumors and decreased metastatic growth. Comparison of this Ets2-specific TAM expression profile with human breast cancer profiles revealed a macrophage gene expression signature that could predict overall survival of estrogen receptor negative patients. In summary, we have identified a critical factor, Ets2, in TAMs that represses a transcriptional program to promote the growth of mammary tumor metastases in the lung. Breast TAMs were isolated from early-stage PyMT-induced mammary tumors expressing Ets2 and also from the tumors with Ets2-deficient TAMs. Since macrophages have also been implicated in normal mammary gland remodeling, normal remeodeling macrophages were also purified from females expressing Ets2 and the ones where Ets2 is deleted in the macrophages. One RNA sample was extracted from each genetic group for gene-expression profiling.
2010-01-05 | E-GEOD-12863 | biostudies-arrayexpress
Project description:Tumor-associated macrophages (TAMs) have immunosuppressive capacity in mouse models of cancer. Here we show that the genetic deletion of the microRNA (miRNA)-processing enzyme DICER in TAMs broadly programs them to a CD11c+MRC1â/low M1-like immunostimulatory phenotype characterized by activated interferon-γ (IFN-γ)/STAT1/IRF signaling. M1-like TAM programming fostered the recruitment of cytotoxic T-cells (CTLs), including tumor-antigen-specific CTLs, inhibited tumor growth, and enhanced the efficacy of PD1 checkpoint blockade. Bioinformatics analysis of TAM transcriptomes identified a limited set of miRNAs putatively involved in TAM programming. Re-expression of Let-7 in Dicer-deficient TAMs was sufficient to partly rescue the M2-like (protumoral) TAM phenotype and abate tumor CTL infiltration. Targeted suppression of DICER activity in TAMs may, therefore, stimulate antitumor immunity and enhance the efficacy of cancer immunotherapy. To explore the role of DICER in the development, activation and immunological functions of TAMs, we crossed homozygous LysM-Cre (Clausen et al., 1999) with Dicerlox/lox (Harfe et al., 2005) mice to obtain mice with myeloid-cell-specific Dicer1 gene deletion (LysM-Cre;Dicerâ/â, referred to as Dâ/â). These mice were then backcrossed to LysM-Cre to obtain the control LysM-Cre; Dicer+/+ mice (referred to as D+/+). Both LysM-Cre and Dicerlox/lox mutations were always homozygous in our experiment. We then inoculated Lewis lung carcinoma (LLC) cells subcutaneously (s.c.) in Dâ/â and control D+/+ mice. Once the tumors were established, we isolated by fluorescence-activated cell sorting (FACS) tumor-associated macrophages (F4/80+ cells).
2016-06-13 | E-GEOD-76356 | biostudies-arrayexpress
Project description:Tumor-associated macrophages (TAMs) shape tumor immunity and therapeutic efficacy. However, it is poorly understood if and how post-translational modifications (PTMs) intrinsically affect the phenotype and function of TAMs. Here, we found that peptidylarginine deiminase 4 (PAD4) manifested the highest expression among common PTM enzymes in TAMs and negatively correlated to clinical response to immune checkpoint blockade (ICB). Genetic and pharmacological inhibition of PAD4 in macrophages prevented tumor progression in tumor-bearing mouse models, accompanied by an increase in macrophage MHC-II expression and T-cell effector function. Mechanistically, PAD4 citrullinated STAT1 at arginine 121 (R121), thereby promoting the interaction between STAT1 and PIAS1; and the loss of PAD4 abolished this interaction, ablating the inhibitory role of PIAS1 in the expression of MHC-II machinery in macrophages and enhancing T-cell activation. Thus, the PAD4-STAT1-PIAS1 axis is a previously unknown intrinsic immune restriction mechanism in macrophages and may serve as a cancer immunotherapy target.
2024-05-22 | PXD049188 | Pride
Project description:Chemotherapies have been shown to enhance anti-tumor immunity, but whether chemotherapies affect tumor-associated macrophages (TAMs) is still unclear. We found TAMs is different before and after chemotherapy by comparing proteomic profiles of TAMs before and after chemotherapy.
2021-02-16 | PXD022674 | Pride
Project description:Chemotherapies have been shown to enhance anti-tumor immunity, but whether chemotherapies affect tumor-associated macrophages (TAMs) is still unclear. We found TAMs is different before and after chemotherapy by comparing proteomic profiles of TAMs before and after chemotherapy.
2021-02-16 | PXD022673 | Pride