MACROPHAGE CD5L IS A NOVEL TARGET FOR CANCER IMMUNOTHERAPY
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE208122 | GEO | 2023/05/12
REPOSITORIES: GEO
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2022-01-12 | GSE190619 | GEO
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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2020-09-07 | GSE105439 | GEO
Project description:Tumor-associated macrophages (TAMs), including anti-tumor M1-like TAMs and pro-tumor M2-like TAMs, are transcriptionally dynamic innate immune cells with diverse roles in lung cancer development. Epigenetic regulators are key controllers of macrophage fate in the spatially heterogeneous tumor microenvironment. Here, we demonstrate that the spatial proximity of histone deacetylase 2 (HDAC2) – overexpressing M2-like macrophages to tumor cells significantly correlates with poor overall survival of lung cancer patients. Suppression of HDAC2 in TAMs altered macrophage polarization, migration, and associated signaling pathways related to interleukin, chemokine, cytokine, and T cell activation. In various co-culture systems of TAMs and cancer cells, suppressing HDAC2 in TAMs results in reduced proliferation and migration and increased apoptosis of cancer cell lines and primary lung cancer cells, as well as attenuated endothelial cell tube length. HDAC2 regulates the pro-tumor macrophage phenotype via acetylation of histone H3 and transcription factor SP1. Myeloidcell–specificc deletion of Hdac2 (Hdac2f/fLysmCre) and pharmacological inhibition of class I HDACs in four different murine lung cancer models (intravenous, intratracheal, tumor relapse, and KrasLA2-driven) induced M2-like to M1-like macrophage phenotypic switching, altered infiltration of CD4 and CD8 T cells and retarded tumor growth and tumor microenvironmental angiogenesis. ThuTAM-specific HDAC2 expression may provide a novel strategy for lung cancer stratification and therapy.
2023-05-16 | GSE227560 | GEO
Project description:To assay the differential gene expression in human THP1-PMA differentiated macrophages expressing human CD5 molecule-like (CD5L) compared to THP1 empty vector control cells. Abstract from associated publication: Lucía Sanjurjo, Gemma Aran, Érica Téllez, Núria Amézaga, Carolina Armengol, Daniel López, Clara Prats and Maria-Rosa Sarrias. CD5L Promotes M2 Macrophage Polarization Through Autophagy-Mediated Upregulation of ID3. Frontiers in Immunology. 9:480. doi: 10.3389/fimmu.2018.00480 (2018). ABSTRACT: CD5L (CD5 molecule-like) is a secreted glycoprotein that controls key mechanisms in inflammatory responses, with involvement in processes such as infection, atherosclerosis, and cancer. In macrophages, CD5L promotes an anti-inflammatory cytokine profile in response to TLR activation. In the present study, we questioned whether CD5L is able to influence human macrophage plasticity, and drive its polarization towards any specific phenotype. We compared CD5L-induced phenotypic and functional changes to those caused by IFN/LPS, IL4 and IL10 in human monocytes. Phenotypic markers were quantified by RT-qPCR and flow cytometry, and a mathematical algorithm was built for their analysis. Moreover, we compared ROS production, phagocytic capacity and inflammatory responses to LPS. CD5L drove cells towards a polarization similar to that induced by IL10. Furthermore, IL10- and CD5L-treated macrophages showed increased LC3II content and colocalization with acidic compartments, thereby pointing to the enhancement of autophagy-dependent processes. Accordingly, siRNA targeting ATG7 in THP1 cells blocked CD5L-induced CD163 and MERTK mRNA and efferocytosis. In these cells, gene expression profiling and validation indicated the upregulation of the transcription factor ID3 by CD5L through ATG7. In agreement, ID3 silencing reversed polarization by CD5L. Our data point to a significant contribution of CD5L-mediated autophagy to the induction of ID3 and provide the first evidence that CD5L drives macrophage polarization.
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2024-01-01 | GSE245440 | GEO
Project description:Prostate cancer is a leading cause of cancer-related deaths of men in the U.S. While localized disease is highly treatable by surgical resection and radiation, cancer that has metastasized remains incurable. Immune cells that primarily scavenge debris, promote prostate cancer angiogenesis and wound repair are M2 Macrophages. They are phenotypically similar to M2 tumor-associated macrophages (M2-TAMs) have been reported to associate with solid tumors and aide in proliferation, metastasis, and resistance to therapy. As an invasive species within the tumor microenvironment, this makes M2-TAMs an ideal therapeutic target in prostate cancer. To identify novel surface antigens expressed on M2-macrophages, we developed a novel method of creating homogenous populations of human macrophages from human CD14+ monocytes in vitro. These homogenous M1 macrophages secrete pro-inflammatory cytokines and our M2 macrophages secrete anti-inflammatory cytokines as well as Vascular Endothelial Growth Factor (VEGF). To identify enriched surface glycoproteins, we then performed solid-phase extraction of N-linked glycopeptides (SPEG) followed by liquid chromatography-tandem Mass Spectrometry (LC-MS/MS) on our homogenous macrophage populations. We discovered novel glycoproteins that are enriched exclusively on human M2-macrophages relative to human M1 macrophages and human CD14+ monocytes. Lastly, we determined if these surface antigens, found enriched on M2 macrophages, were also expressed in human metastatic castrate-resistant prostate cancer (mCRPC) tissues. Using mCRPC tissues from rapid autopsies, we were able to determine M2-macrophage infiltration by using immunohistochemistry and flow cytometry. These findings highlight the presence of macrophage infiltration in human mCRPC but also surface antigens that could be used for prognosis of localized disease and for targeting strategies.
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