Effect of CD137 (4-1BB) triggering on human monocytes
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ABSTRACT:
PROVIDER: PRJNA718345 | ENA |
REPOSITORIES: ENA
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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: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: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 but also innate immune cells such as natural killer cells, neutrophils, and monocytes can express CD137. In order to delineate properties of monocytes expressing CD137, RNAseq of CD137HI vs CD137LO expression monocytes was performed.
2021-06-17 | GSE171109 | GEO
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:CD137 (4-1BB) is a member of the TNFR superfamily that represents a promising target for cancer immunotherapy. Recent insights into the function of TNFR agonist antibodies implicate epitope, affinity, and IgG subclass as critical features, and these observations help explain the limited activity and toxicity seen with clinically tested CD137 agonists. Here we describe the preclinical characterization of CTX-471, a fully human IgG4 agonist of CD137 that engages a unique epitope that is shared by human, cynomolgus monkey, and mouse and is associated with a differentiated pharmacology and toxicology profile. In vitro, CTX-471 increased IFN-γ production by human T cells in an FcγR-dependent manner, displaying an intermediate level of activity between two clinical-stage anti-CD137 antibodies. In mice, CTX-471 exhibited curative monotherapy activity in various syngeneic tumor models and showed a unique ability to cure mice of very large (~500 mm3) tumors compared to validated antibodies against checkpoints and TNFR superfamily members. Extremely high doses of CTX-471 were well-tolerated, with no signs of hepatic toxicity. Collectively, these data demonstrate that CTX-471 is a unique CD137 agonist that display an excellent safety profile and an unprecedented level of monotherapy efficacy against very large tumors.
2020-01-30 | GSE144473 | GEO
Project description:Costimulation of T cells with agonist antibodies targeting 4-1BB (CD137) improves antitumor immune responses in preclinical studies, but clinical development has been hampered by on-target, off-tumor toxicity. Here, we report the development of a tumor-anchored ɑ4-1BB agonist, termed ɑ4-1BB-LAIR, which consists of an ɑ4-1BB antibody fused to the collagen binding protein mLAIR1. Combination treatment with an antitumor antibody (TA99) displayed only modest efficacy, but surprisingly cured >90% of mice upon depletion of CD4+ cells. We elucidated two mechanisms of action for this synergy: ɑCD4 increased priming and activation in the tumor draining lymph node , and TA99 + ɑ4-1BB-LAIR supported the cytotoxic program of these newly primed CD8+ T cells within the tumor microenvironment. Replacement of ɑCD4 with ɑCTLA-4, a more clinically relevant agent to enhance T cell priming, produces equivalently high cure rates while generating significantly more robust immunological memory against secondary tumor rechallenge.
2023-01-30 | GSE223087 | GEO
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.
2016-06-30 | GSE60199 | GEO
Project description:In the present study, we demonstrate that NOD2 receptor triggering by muramyl dipeptide converts blood inflammatory Ly6Chigh monocytes into patrolling Ly6Clow monocytes. Muramyl dipeptide administration to Nr4a1-/- mice, which lack Ly6Clow monocytes, and to Ly6Clow-depleted mice leads to the emergence of blood patrolling monocytes expressing phenotypic profile of typical Ly6Clow monocytes, including high expression of CX3CR1 and LFA1. Furthermore using intravital microscopy in live animal models of inflammatory diseases, we observed that converted Ly6Chigh monocytes are capable of patrolling the endothelium of blood vessels and their presence contributes to reduce the inflammatory response following muramyl dipeptide injection.
2019-01-14 | GSE101496 | 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