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Expression data from in vitro-induced non-hypoxic tumour associated macrophages (TAMs)

ABSTRACT: Active immunotherapy is a promising strategy for anti-angiogenic cancer therapy. Recently, we have reported that a vaccine using human umbilical vein endothelial cells (HUVECs) induced specific anti-endothelial immune responses in the most of immunized patients, and resulted in tumor regression in some patients with recurrent malignant brain tumors, whereas not in colorectal cancer patients. In this study, we hypothesized that non-hypoxic perivascular tumor associated macrophages (TAMs) in colorectal cancer, but not in glioblastoma, might negatively alter the therapeutic efficacy of anti-angiogenic active immunotherapy. To test this hypothesis, we examined global gene expression profiles of non-hypoxic macrophages stimulated in vitro by soluble factors released from tumor cells of human glioblastoma U-87MG (‘brain TAMs’) or colorectal adenocarcinoma HT-29 (‘colon TAMs’). Murine non-hypoxic TAMs were induced in vitro by incubation with soluble factors released from human cancer cell lines U-87MG ('brain TAMs') or HT-29 ('colon TAMs'), for RNA extraction and subsequent hybridization on Affymetrix microarrays. To evaluate homogeneous macrophage populations at different tumour developmental stages, RNA aliquots of control macrophages and TAMs obtained at five different time-points, i.e. 8h, 16h, 24h, 32h and 40h, were pooled and used for screening of differentially expressed genes. The experiments for TAMs as well as for control unstimulated macrophages were performed in triplicates.

ORGANISM(S): Mus musculus

SUBMITTER: Yurai Okaji

PROVIDER: E-GEOD-18804 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Expression data from in vitro-induced non-hypoxic tumour associated macrophages (TAMs)

Project description:Active immunotherapy is a promising strategy for anti-angiogenic cancer therapy. Recently, we have reported that a vaccine using human umbilical vein endothelial cells (HUVECs) induced specific anti-endothelial immune responses in the most of immunized patients, and resulted in tumor regression in some patients with recurrent malignant brain tumors, whereas not in colorectal cancer patients. In this study, we hypothesized that non-hypoxic perivascular tumor associated macrophages (TAMs) in colorectal cancer, but not in glioblastoma, might negatively alter the therapeutic efficacy of anti-angiogenic active immunotherapy. To test this hypothesis, we examined global gene expression profiles of non-hypoxic macrophages stimulated in vitro by soluble factors released from tumor cells of human glioblastoma U-87MG (‘brain TAMs’) or colorectal adenocarcinoma HT-29 (‘colon TAMs’).

2012-04-01 | GSE18804 | GEO

An Ets2-specific transcriptional program in tumor-associated macrophages promotes metastasis

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

Spatiotemporal single-cell transcriptomics in mouse and human to investigate TAM evolution during GBM progression

Project description:Glioblastoma (GBM) is the most common and malignant primary brain tumor. Although immunotherapy has shown promise in certain cancer types, it has not been effective against GBM, largely due to its highly immunosuppressive tumor microenvironment (TMEs), which is rich in tumor-associated macrophages/microglia (TAMs). TAMs in late-stage GBM contribute to T-cell exhaustion and worsen prognosis, but the role of TAMs in earlier stages of tumor development is unclear. By employing genetically engineered mouse models and human samples, we used spatiotemporal single-cell transcriptomics to investigate TAM evolution during GBM progression.

2023-09-06 | GSE241037 | GEO

pH-gated nanoparticles selectively regulate lysosomal function of tumour-associated macrophages for cancer immunotherapy

Project description:Tumour-associated macrophages (TAMs), as one of the most abundant and phagocytic tumour-infiltrating immune cells, play a pivotal role in tumour antigen clearance and immune suppression. M2-like TAMs present a heightened lysosomal acidity and protease activity, which limits the function of antigen cross-presentation. How to selectively reprogram the antigen-destroying TAMs to a restorative phenotype for efficient anti-tumour immunity is challenging. Here, we report a pH-gated nanoadjuvant (PGN) that selectively targets the lysosomes of M2-like TAMs in tumours rather than the corresponding organelles from macrophages in healthy tissues. Enabled by the PGN nanotechnology, M2-like TAMs are specifically switched to M1-like phenotypes with tuned-down lysosomal function featured by attenuated lysosomal acidity and cathepsin activity for improved antigen cross-presentation, thus provoking adaptive immune response and sustained tumour regression. Our findings provide new insights into how to specifically regulate lysosomal function of TAMs for efficient cancer immunotherapy.

2023-08-29 | PXD044911 | Pride

Therapeutic Exosomal Vaccine for Enhanced Cancer Immunotherapy by Mediating Tumor Microenvironment

Project description:Tumor immunotherapy has been convincingly demonstrated as a feasible approach for treating cancers. Although promising, however, the immunosuppressive tumor microenvironment (TME) has been recognized as a major obstacle in tumor immunotherapy. It is highly desirable to release an immunosuppressive “brake” for improving cancer immunotherapy. Among tumor-infiltrated immune cells, tumor-associated macrophages (TAMs) play an important role in the growth, invasion and metastasis of tumors. The polarization of TAMs (M2) into the M1 type can alleviate the immunosuppression of the TME and enhance the effect of immunotherapy. Inspired by this, we constructed a therapeutic exosomal vaccine from antigen-stimulated M1-type macrophages (M1OVA-Exos). M1OVA-Exos are capable of polarizing TAMs into M1 type through downregulation of the Wnt signaling pathway. Mediating the TME further activates the immune response and inhibits tumor growth and metastasis via the exosomal vaccine. Our study provides a new strategy for the polarization of TAMs, which augments cancer vaccine therapy efficacy.

2022-01-12 | GSE190619 | GEO

Targeting IRG1 in tumor-associated macrophages for cancer therapy

Project description:Immune-responsive gene 1 (IRG1) is a mitochondrial aconitate decarboxylase and can produce the immunomodulatory metabolite itaconic acid (ITA). However, its role in modulating the function of tumor-associated macrophages (TAMs) remains elusive. Here, we show that IRG1 is expressed in TAMs in human tumors and mouse models of cancer. Tumor cells induce Irg1 expression in macrophages which dampens the inflammatory response and restricts M1-like TAM polarization. In contrast, Irg1-deficent macrophages acquire more proinflammatory M1-like features, promote immunogenic antigen presentation, and enhance cytotoxic T cell infiltration into tumor sites. Consequently, Irg1 deficiency suppresses the growth of mouse syngeneic tumors, including melanoma, colorectal cancer, breast cancer, and pancreatic cancer. Irg1-deficient macrophages not only dictate the tumoricidal effect but enhance the efficacy of anti-PD(L)1 immunotherapy. In conclusion, our data identify IRG1 as a myeloid immune check point gene and foster the development of genetic or pharmacologic targeting of IRG1 for skewing macrophages toward an anti-tumor phenotype to treat a broad spectrum of cancer.

2023-05-01 | GSE210845 | GEO

Cyr61 promotes CD204 expression and migration of macrophages via MEK/Erk pathway in the microenvironment of human esophageal squamous cell carcinoma

Project description:The authors previously suggested that CD204 was a useful marker for tumor-associated macrophages (TAMs) of esophageal squamous cell carcinoma (ESCC). In this study, they discovered that within ESCC microenvironment not only cancer cells but also TAMs expressed cysteine-rich, angiogenic inducer, 61 (Cyr61), induced by conditioned media of ESCC cells. Levels of Cyr61 expression were associated with CD204+ macrophage infiltration in ESCC tissue. Cyr61 promoted CD204 expression and migration of macrophages via MEK/Erk pathway in vitro.

2014-10-08 | GSE59471 | GEO

Exome sequencing of KP and KPM lung tumors.

Project description:Immune checkpoint blockade (ICB) with PD1 or PDL1 antibodies has been approved for the treatment of non-small cell lung cancer (NSCLC). However, only a minority of the patients respond and sustained remissions are rare. Both chemotherapy and anti-angiogenic drugs may improve tumor response to ICB in mouse models and patients with cancer. Here, we used genetically engineered mouse models of KrasG12D/p53null NSCLC, including a mismatch repair-deficient variant (KrasG12D/p53null/Msh2null) with higher mutational burden, and longitudinal imaging to study tumor response and resistance to combinations of ICB, anti-angiogenic therapy, and chemotherapy. Anti-angiogenic blockade of VEGFA and angiopoietin-2 markedly slowed progression of established tumors but, contrary to findings in other mouse cancer models, addition of a PD1 or PDL1 antibody was not beneficial and even accelerated progression of some of the tumors. We found that anti-angiogenic treatment facilitated tumor infiltration by PD1+ regulatory T cells (T-regs), which were more efficiently targeted by the PD1 antibody than CD8+ T cells. Both tumor-associated macrophages (TAMs) of bone-marrow origin, which are CSF1R-dependent, and TAMs of alveolar origin, which are sensitive to cisplatin, contributed to establishing a TGFB-rich tumor microenvironment that supported PD1+ T-regs. Dual TAM targeting with a combination of cisplatin and a CSF1R inhibitor fully abated T-regs, redirected the PD1 antibody to CD8+ T cells, and improved the efficacy of anti-angiogenic immunotherapy, achieving regression of the majority of the tumors.

2021-08-15 | GSE169195 | GEO

Expression profile comparison of enriched bone marrow-derived tumor associated macrophages, tumor-associated alveolar macrophages, CD4 T cells, and total tumor-derived cells in lung cancer models with or without anti-PD1 and anti-VEGFA/ANGPT2 treatments.

2021-08-15 | GSE169194 | GEO

DICER controls macrophage polarization and tumor response to immunotherapy

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-Î³ (IFN-Î³)/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

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