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Differential gene expression in CD137HI vs CD137LO human healthy donor monocytes

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE171109 | GEO | 2021/06/17

REPOSITORIES: GEO

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Effect of CD137 (4-1BB) triggering on human monocytes

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

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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.

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Effect of CD137 (4-1BB) triggering on human monocytes

Project description:Effect of CD137 (4-1BB) triggering on human monocytes

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Differentiated agonistic antibody targeting CD137 eradicates large tumors without hepatotoxicity

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Project description:We observed self-activation of SKM-CAR-T cells which target novel mesothelioma antigen. CAR-T with CD28 costimulatory domain showed signs of exhaustion while those with 4-1BB costimulatory domain did not. Changes in the gene expression by substituting CD28 co-stimulatory domain to 4-1BB co-stimulatory domain was investigated.

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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.

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