Expression analysis of tumor-associated macrophages from primary tumor and metastatic lung
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE96944 | GEO | 2018/07/26
REPOSITORIES: GEO
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Project description:Tumor-associated macrophages (TAMs) are key components of the tumor microenvironment (TME) which can either promote tumor progression (M2) or induce antitumor immunity (M1). The hypothesis of our study is that the expression of FOLR2 is associated with an M2-like macrophage profile. The main goal of this study is to compare the transcriptomic profile of FOLR2 positive and FOLR2 negative TAMs obtained from the ascites of C57BL/6 mice bearing ovarian ID8 intraperitoneal tumors. Abstract: The immunosuppressive tumor microenvironment (TME) represents a major barrier for effective immunotherapy. Tumor-associated macrophages (TAMs) are highly heterogeneous and plastic cell components of the TME which can either promote tumor progression (M2-like) or boost antitumor immunity (M1-like). Selective targeting of the pro-tumorigenic subset of TAMs represents an attractive therapeutic strategy. Here, we demonstrate that a subset of TAMs that expressing folate receptor β (FRβ) possess an immunosuppressive, tumor-promoting M2-like profile, while FRβ negative TAMs feature pro-inflammatory M1 macrophage properties. In syngeneic tumor mouse models, the administration of FRβ-targeted chimeric antigen receptor (CAR) T-cells mediated elimination of FRβ+ TAMs in the TME, which resulted in an enrichment of pro-inflammatory monocytes, an influx of endogenous tumor-specific CD8+ T-cells, delayed tumor progression, and prolonged survival. Preconditioning of the TME with FRβ-specific CAR T-cells also improved the effectiveness of tumor-directed anti-mesothelin CAR T-cells, while simultaneous co-administration of both CAR products did not. Thus, CAR T-cell-mediated depletion of immunosuppressive M2-like TAMs incites a pro-inflammatory TME that broadens endogenous antitumor immunity and limits tumor progression, highlighting the pro-tumor role of FRβ+ TAMs in the TME and the therapeutic implications of TAM-depleting agents as preparative adjuncts to conventional immunotherapies that directly target tumor antigens.
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Project description:Metastasis is the primary cause of mortality in breast cancer patients. Tumor associated macrophages (TAMs) are active collaborators in mediating several steps of the tumor metastatic cascade, but the molecular details governing this collaboration remain ill-defined. Colony Stimulating Factor 1 (CSF1), a factor critical for macrophage differentiation and survival, functions to recruit TAMs to the primary tumor site, and anti-CSF1 therapies are in clinical trials.In this study, we tested the effect of inhibiting CSF1 signaling in macrophages on gene expression in metastatic tumor cells in mouse models of breast cancer metastasis. Tumor cells were sorted from lung metastases from control and CSF1R inhibitor treated mice. Several pro-tumor processes were significantly affected by CSF1R inhibitor treatment, including angiogenesis and tumor cell proliferation. In addition, a 29 gene signature derived from this data could retrospectively predict survival in a cohort of luminal B breast cancer patients. Collectievly, our results highlight the utility of employing CSF1R inhibitors for the treatment of metastatic breast cancer. GFP tagged MVT1 metastatic mammary tumor cells were injected intravenously into FVB/N mice. Mice were gavaged with the CSF1R inhibitor GW2580 or vehicle starting one week post injection. GFP tagged tumor cells were sorted from metastatic tumor bearing lungs 1 and 2 weeks post injection from 2 vehicle treated mice for each. These are denoted 1_week_WT and 2_week_WT respectively. GFP tagged tumor cells were simultaneously sorted from mice gavaged with GW2580. These samples are denoted 2_week_GW. RNA was extracted and gene expression profiling was performed using the Affymetrix Mouse Genome 430 2.0 Array platform.
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Project description:Metastasis is the primary cause of mortality in breast cancer patients. Tumor associated macrophages (TAMs) are active collaborators in mediating several steps of the tumor metastatic cascade, but the molecular details governing this collaboration remain ill-defined. Colony Stimulating Factor 1 (CSF1), a factor critical for macrophage differentiation and survival, functions to recruit TAMs to the primary tumor site, and anti-CSF1 therapies are in clinical trials.In this study, we tested the effect of inhibiting CSF1 signaling in macrophages on gene expression in metastatic tumor cells in mouse models of breast cancer metastasis. Tumor cells were sorted from lung metastases from control and CSF1R inhibitor treated mice. Several pro-tumor processes were significantly affected by CSF1R inhibitor treatment, including angiogenesis and tumor cell proliferation. In addition, a 29 gene signature derived from this data could retrospectively predict survival in a cohort of luminal B breast cancer patients. Collectievly, our results highlight the utility of employing CSF1R inhibitors for the treatment of metastatic breast cancer.
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Project description:Studies have revealed that TAMs can promote tumor immune escape, tumor growth, angiogenesis, and metastasis. Targeting TAMs to reset M2 towards the anti-tumor M1 phenotype is considered as a promising strategy in cancer immunotherapy. Interestingly, we found in the current investigation that the expression level of CAMKII mRNA in M2 was much higher than that in M1 . Based on this finding, the CAMKII specific inhibitor KN93 was used to explore the effect on bone marrow-derived macrophages. Strikingly, KN93 significantly increased the expression of CD86 (M1 marker) and reduced CD206 (M2 marker) expression in a concentration-dependent manner by the flow cytometry. To further verify whether KN93 could affect the polarization of BMDMs at the transcriptome level, we cultured BMDMs with KN93 (5 μM or 10 μM) or PBS for 24 h and analyzed the global transcriptional profile in cells through RNA sequencing. Compared with control cells, KN93-treated BMDMs expressed significantly higher levels of M1-related transcriptional factors, cytokines and other molecules and lower levels of M2-associated transcriptional factors, cytokines and other molecules. Conclusively, these results demonstrate that targeting CAMKII reprogramed M2 toward the M1 phenotype in vitro.
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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.
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