Characterization of tumor associated macrophages (TAM) in the tumor microenvironment of human melanoma
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE171277 | GEO | 2021/08/09
REPOSITORIES: GEO
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Project description:Tumor cells attract and dynamically interact with monocytes/macrophages, one of the more abundant cell types in the tumor microenvironment, to subvert their differentiation into tumor associated macrophages (TAMs), which mainly promote immunosuppression and neoplastic progression, but the mechanisms governing their protumoral activity are not completely understood. Thus, identifying molecular pathways promoted by macrophages that could be responsible for immune evasion and tumor malignicity may provide new therapeutic targets to improve the efficacy of immunotherapy of cancer.
2023-12-11 | GSE242674 | GEO
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: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
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+MRC1−/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.
2016-06-13 | GSE76356 | GEO
Project description:To test the difference genes expression of TAMs obtained from orthotopically implanted hepa1-6 tumors in C57BL/6 mice.Isolated TAMs were obtained from orthotopically implanted hepa1-6 tumors in C57BL/6 mice. Specimens were minced with scissors and digested by incubation for 1 h at 37°C in high-glucose DMEM (Life Technologies, CA) containing 0.1% collagenase IV (Sigma). After being washed in medium plus 10% FBS, the cell suspension was forced through a graded series of meshes to obtain single-cell suspensions and centrifuged at 400 g for 30–40 minutes at 18–20°C on layers of Lympholyte-M (Cedarlane Labs, Burlington, Ontario, Canada), after which the upper layer was removed, thus leaving the lymphocyte layer undisturbed at the interface. TAMs were sorted using Fluorescence-activated cell sorting (FACS, Becton Dickinson, Franklin Lakes, NJ) with CD45+, CD11b+, and F4/80+ (Becton Dickinson) according to the protocol listed at http://www.immgen.org/Protocols/ImmGen%20Cell%20prep%20and%20sorting%20SOP.pdf . TAMs growing in DMEM supplemented with 10% FBS were tested to determine their biological characteristics. We used microarrays to detail the global programme of gene expression and identified vehicle-TAM and treated-TAM during this process.
2017-02-28 | GSE95406 | GEO
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:Heme-activation of NRF2 is a strong anti-inflammatory signal in macrophages, and analyses in this study indicated that the expressed transcriptome in heme-TAMs was consistently enriched for NRF2 target genes. We have therefore delineated the role of NRF2 in a series of experiments with Nrf2 knockout BMDMs, leading to a locked NRF2-inactive state, and macrophages with a knockout of the cytoplasmic NRF2 capture protein KEAP1, leading to a locked NRF2-active state, irrespective of the presence or absence of heme. To demonstrate that activated NRF2 is sufficient to drive heme-TAM transformation, we analyzed Keap1 knockout macrophages.
2024-01-03 | GSE236997 | GEO
Project description:In order to assess whether differences in the transcriptomic profile of human tumor-associated macrophages vs. alveolar macrophages from adjacent non-tumor-tissue (GSE162669) were caused by factors secreted by tumor cells, primary human monocyte-derived macrophages (MDMs) were polarized towards a TAM-like phenotype by cultivating them in tumor cell-conditioned medium. A genome-wide comparison by bulk RNA-Seq confirmed a high similarity of ex vivo TAMs and in vitro polarized TAM-like macrophages. Other polarization schemes (M1: LPS/IFN-gamma, M2: IL10 or IL4) did not lead to similar transcriptomic changes. For details, see Hoppstädter et al., 2021 (doi:10.1016/j.ebiom.2021.103578).
2021-09-25 | GSE162698 | GEO
Project description:Hematopoietic stem/progenitor cells (HS/PCs) were transduced with lentiviral vectors overexpressing OFP and either miR-511-3p or a control, mutated miRNA sequence (miR-511-3p-mut). The transduced HS/PCs were then transplanted in recipient C57BL/6 mice. Tumors (Lewis lung carcinomas, LLC) were injected s.c. 4 weeks after HS/PC transplant. Lentiviral vector-transduced (OFP+), tumor-associated macrophages (TAMs) were isolated 4 weeks after LLC injection by fluorescence-activated cell sorting. Gene expression profiles of TAMs overexpressing either miR-511-3p or miR-511-3p-mut were obtained from 3 independent biological samples/each. Gene expression profiles of miRNA-overexpressing TAMs were then compared with the gene expression profiles of wild-type TAMs isolated from LLCs grown in nontransplanted C57BL/6 mice; the latter TAMs were subfractioned into MRC1+CD11c(low) or CD11c+MRC1(low) subsets before RNA isolation and analysis. Comparison of gene expression profiles of TAMs revealed that miR-511-3p overexpression tunes down the expression of multiple genes that are classically upregulated in protumoral MRC1+CD11c(low) TAMs. TAMs were isolated from Lewis lung carcinomas grown s.c. in C57BL/6 mice.
2012-04-01 | E-GEOD-34903 | biostudies-arrayexpress
Project description:Long recognized as an evolutionarily ancient cell type involved in tissue homeostasis and immune defense against pathogens, macrophages are being rediscovered as regulators of several diseases including cancer. Here we show that in mice, mammary tumor growth induces the accumulation of tumor-associated macrophages (TAMs) that are phenotypically and functionally distinct from mammary tissue macrophages (MTMs). TAMs express the adhesion molecule Vcam1 and proliferate upon their differentiation from inflammatory monocytes, but do not exhibit an “alternatively activated” phenotype. TAM differentiation depends on the transcriptional regulator of Notch signaling, RBPJ; and TAM, but not MTM, depletion restores tumor-infiltrating cytotoxic T cell responses and suppresses tumor growth. These findings reveal the ontogeny of TAMs and a discrete tumor-elicited inflammatory response, which may provide new opportunities for cancer immunotherapy. MMTV-PyMT mice (Jackson Laboratory) were backcrossed to the C57BL/6 background for 10 generations. Rbpjfl/fl mice were provided by Tasuku Honjo and crossed to CD11ccre mice provided by Boris Reizis. Littermate controls were used in all experiments when possible. All mice were maintained in a specific pathogen-free facility and animal experimentation was conducted in accordance with institutional guidelines. In the MMTV-PyMT spontaneous mammary tumor model, we found the key Notch transcriptional regulator, RBPJ, to be required for TAM terminal differentiation from inflammatory monocytes. The bulk myeloid cell population that remains in CD11cCreRbpj fl/fl mice (the cells in "Rbpj KO" samples), represents monocytes that have begun their differentiation into macrophages, but are unable to terminally differentiate due to the lack of Rbpj.
2014-04-18 | E-GEOD-56755 | biostudies-arrayexpress