CD137 promotes bone metastasis of breast cancer by enhancing the migration and osteoclast differentiation of monocytes/macrophages
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PROVIDER: PRJNA533593 | ENA |
REPOSITORIES: ENA
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Project description:Rationale: Bone is the most common metastatic site of breast cancer. CD137(4-1BB), a member of the tumor necrosis factor (TNF) receptor superfamily, is mainly expressed in activated leukocytes. Previous study demonstrates the effect of CD137-CD137L bidirectional signaling pathway on RANKL-mediated osteoclastogenesis. However, the role of CD137 in bone metastasis of breast cancer needs further study. Methods: Stable monocyte/macrophage cell lines with Cd137 overexpression and silencing were established. Western blot, real-time PCR, transwell and tartrate-resistant acid phosphatase staining were used to detect the regulatory effect of CD137 on migration and osteoclastogenesis of monocytes/macrophages in vitro. Spontaneous bone metastasis mouse model was established, bioluminescent images, immunohistochemistry and histology assay were performed to detect the function of CD137 in bone metastasis in vivo. Results: We found that CD137 promotes the migration of monocytes/macrophages to tumor microenvironment by upregulating the expression of Fra1. It also promoted the differentiation of monocytes/macrophages into osteoclasts at the same time, thus providing a favorable microenvironment for the colonization and growth of breast cancer cells in bone. Based on these findings, a novel F4/80-targeted liposomal nanoparticle encapsulating the anti-CD137 Ab blocking antibody (NP-aCD137 Ab-F4/80) was synthesized. This nanoparticle could inhibit both bone and lung metastases of 4T1 breast cancer cells with high efficacy in vivo. In addition, it increased the therapeutic efficacy of Fra1 inhibitor on tumor metastasis. Conclusions: Taken together, these findings reveal the promotion effect of macrophage/monocyte CD137 on bone metastases and provide a promising therapeutic strategy for metastasis of breast cancer.
2019-06-20 | GSE130013 | GEO
Project description: Not available
| S-EPMC6568184 | biostudies-literature
Project description:The cell surface glycoprotein CD137, which is also known as 4-1BB, belongs to the group of co-stimulatory immune receptors and is a member of the TNF receptor superfamily (TNFRSF). It is preferentially found on activated T-cells and regulatory T-cells. In T-cells, CD137-crosslinking delivers a potent co-stimulatory signal as it promotes T-cell proliferation, formation of memory cells and enhances survival. Despite numerous studies investigating the effects of co-stimulatory CD137 in T-cells, little is known regarding the role of CD137 in human monocytes/macrophages. To investigate the effect of CD137 triggering on human monocytes, monocytes were isolated and treated with an agonistic CD137 mAb and subsequently analyzed by RNA-seq.
2021-06-17 | GSE171108 | GEO
Project description:CD137 cis-costimulation is superior to trans-costimulation at inducing transcriptomic differences in T-cell proliferation and DNA repair programs We used microarrays to detail differentially expressed genes of cis- and trans CD137-costimulated CD8 T cells with respect to CD3-TCR stimulation
2021-09-28 | GSE158041 | GEO
Project description:Conversion of monocytes to osteoclasts is a unique terminal differentiation process within the hematopoietic system involving differentiation and massive cell fusion. Here we focused on DNA methylation changes during osteoclastogenesis. Hypermethylation and hypomethylation changes took place in several thousand genes, including all relevant functional categories in osteoclast differentiation and function. Comparison between the DNA methylation levels of CD14+ monocytes and derived osteoclast from 3 female donors. Bisulphite converted DNA from the 6 samples was hybridised to the Illumina Infinium 450k Human Methylation Beadchip
2013-08-30 | E-GEOD-46648 | biostudies-arrayexpress
Project description:The contribution of monocyte-derived dendritic cells (DC) to an immune response is essential for the elimination of pathogens. In vitro DC can be generated by treatment of monocytes with GM-CSF + IL-4 but it is unknown what stimuli induce the differentiation of monocytes to DC in vivo. CD137L-DC are human monocyte-derived DC that are generated by CD137 ligand (CD137L) signaling. Since CD137 is only expressed at sites of inflammation it would be a suitable signal for the induction of monocyte-derived DC. Here we report on gene expression analysis of CD137L-DC, immature and mature classical DC, monocytes and macrophages which indicates that CD137L-DC have a gene signature that is most similar to that of classical DC. Additionally, CD137L-DC signature genes are highly enriched in monocyte-derived DC which were isolated from sites of inflammation. Also cell surface marker expression and cytokine secretion of CD137L-DC are highly similar to that of inflammatory monocyte-derived DC. CD137L-DC express high levels of adhesion molecules, display strong attachment and employ the adhesion molecule ALCAM to stimulate T cell proliferation. This study identifies a physiological stimulus for the generation of monocyte-derived DC in vivo. A total of 30 expression profiles were obtained, on 6 APC subtypes from 5 different donors
2016-06-30 | E-GEOD-60199 | biostudies-arrayexpress
Project description:Osteoclasts are absorptive cells and play a critical role in homeostatic bone remodeling and pathological bone resorption. Emerging evidence suggests an important role for epigenetic regulation of osteoclastogenesis. In this study, we investigated the role of DOT1L, which regulates gene expression epigenetically by histone H3K79 methylation during osteoclast formation. DOT1L and H3K79me2 levels were upregulated during osteoclast differentiation. Small molecule inhibitor- (EPZ5676 or EPZ004777) or short hairpin RNA-mediated reduction in DOT1L expression promoted osteoclast differentiation and resorption. DOT1L inhibition also increased osteoclast area and accelerated bone mass reduction in a mouse ovariectomy (OVX) model of osteoporosis. DOT1L inhibitors did not alter osteoblast differentiation in vitro and in vivo. Proteomics data, together with bioinformatics analysis, revealed that DOT1L inhibition altered reactive oxygen species (ROS) generation, autophagy activation, and cell fusion-related protein expression. ROS generation increased, and autophagy activation and cell migration ability enhancement were verified subsequently by flow cytometry and transwell migration assays. DOT1L inhibition increased NFATc1 nuclear translocation and NF-κB activation and strengthend osteoclast fusion and expression of resorption-related protein CD9, and MMP9 in osteoclasts derived from RAW264.7. Our findings support a new mechanism of DOT1L-mediated H3K79me2 epigenetic regulation of osteoclast differentiation, implicating DOT1L as a new therapeutic target for osteoclast dysregulation-induced disease.
2018-01-24 | PXD006448 | Pride
Project description:Enhancing NK cell-based cancer immunotherapy by overcoming immunosuppression is an unmet goal. Here, we demonstrate the ability of the anti-CD137 agonist urelumab for overcoming TGF-β-mediated inhibition of human NK-cell proliferation and sustained anti-tumor function. Transcriptomic, immunophenotypic and functional analyses evidenced that CD137 costimulation modified the transcriptional program induced by TGF-β on activated NK cells by limiting SMAD4-dependent inhibition of pro-proliferative (CD25, cMyc), activating (NKG2D, CD16) and effector (Granzyme B, IFNγ) molecules while maintaining SMAD4-independent acquisition of tumor-retention features (CXCR3, CD103). Activated NK cells cultured in the presence of TGF-β1 and CD137 agonist showed preserved antibody-dependent cytotoxicity against cancer cells, recovered CCL5 and IFNγ secretion and gained the capacity for producing IL-9 upon restimulation. Treatment of breast tumor-derived multicellular cultures with trastuzumab and urelumab recapitulated CD137 induction and fostered tumor-infiltrating CD16+ NK cell persistence. Our data reveals CD137 as a targetable checkpoint for overturning TGF-β constrains on NK cell anti-tumor responses.
2021-09-10 | GSE143375 | GEO
Project description:Enhancing NK cell-based cancer immunotherapy by overcoming immunosuppression is an unmet goal. Here, we demonstrate the ability of the anti-CD137 agonist urelumab for overcoming TGF-β-mediated inhibition of human NK-cell proliferation and sustained anti-tumor function. Transcriptomic, immunophenotypic and functional analyses evidenced that CD137 costimulation modified the transcriptional program induced by TGF-β on activated NK cells by limiting SMAD4-dependent inhibition of pro-proliferative (CD25, cMyc), activating (NKG2D, CD16) and effector (Granzyme B, IFNγ) molecules while maintaining SMAD4-independent acquisition of tumor-retention features (CXCR3, CD103). Activated NK cells cultured in the presence of TGF-β1 and CD137 agonist showed preserved antibody-dependent cytotoxicity against cancer cells, recovered CCL5 and IFNγ secretion and gained the capacity for producing IL-9 upon restimulation. Treatment of breast tumor-derived multicellular cultures with trastuzumab and urelumab recapitulated CD137 induction and fostered tumor-infiltrating CD16+ NK cell persistence. Our data reveals CD137 as a targetable checkpoint for overturning TGF-β constrains on NK cell anti-tumor responses
2021-09-10 | GSE156199 | GEO