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Immune modulation with RANKL-blockade through denosumab treatment in cancer patients

ABSTRACT: Immune modulation with RANKL-blockade through denosumab treatment in cancer patients

PROVIDER: PRJNA1045990 | ENA |

REPOSITORIES: ENA

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Immune modulation with RANKL-blockade through denosumab treatment in cancer patients

Project description:Denosumab is a fully human monoclonal antibody that binds receptor activator of nuclear factor-κB ligand (RANKL) and is routinely administered to cancer patients to reduce the incidence of new bone metastasis. RANK-RANKL regulates bone turnover by controlling osteoclast recruitment, development, and activity. However, this interaction also can regulate a broad range of immune cells including dendritic cells and medullary thymic epithelial cells (mTECs). Inhibition of the latter results in reduced thymic negative selection of T cells and could enhance the generation of tumor-specific T cells. We examined whether administering denosumab could modify modulate circulating immune cells in cancer patients. Blood was collected from 23 prostate cancer patients and 3 renal cell carcinoma patients, who provided written informed consent, with advanced disease who were receiving denosumab, prior to and during denosumab treatment. Using high-dimensional mass cytometry, we found that denosumab treatment by itself induced modest effects on circulating immune cell frequency and activation. We also found minimal changes in the circulating T cell repertoire and the frequency of new thymic emigrants with denosumab treatment. However, when we stratified patients by whether they were receiving chemotherapy and/or steroids, patients receiving these concomitant treatments showed significantly greater immune modulation, including an increase in the frequency of NK cells early and classical monocytes later. We also saw broad induction of CTLA-4 and TIM3 expression in circulating lymphocytes and some monocyte populations. These findings suggest that denosumab treatment by itself has modest immunomodulatory effects, but when combined with conventional cancer treatment, can lead to the induction of immunologic checkpoints.

2024-04-10 | GSE248774 | GEO

RANKL regulates testicular cancer growth and Denosumab has tumor suppressive effects in GCNIS and advanced seminoma

Project description:Testicular germ cells tumors (TGCTs) have a high sensitivity to cisplatin-based chemotherapy and a high cure rate, although with possible serious adverse effects. In the search for tumor suppressive drugs, the RANKL inhibitor Denosumab, used to treat osteoporosis came up as a candidate since RANKL signaling was recently identified in the testis. RANKL signals through the receptor RANK and this signaling is antagonized by the decoy receptor OPG. Here, we demonstrate expression of RANKL, RANK, and OPG in germ cell neoplasia in situ (GCNIS), TGCTs, and TGCT-derived cell lines. RANKL inhibition reduced proliferation of seminoma-derived TCam-2 cells but had no effect on embryonal carcinoma-derived NTera2 cells in vitro. Denosumab did not potentiate the effect of cisplatin treatment in vitro but inhibition of RANKL in vivo resulted in reduced tumor growth in a TCam-2 but not a NTera2 xenograft model. Moreover, Denosumab treatment decreased proliferation in human testicular GCNIS tissue culture in vitro. In TGCT patients, serum RANKL was not linked with tumor burden, relapse, or other prognostic markers. In conclusion, this study shows that the RANKL signaling system is expressed in GCNIS and seminoma where RANKL inhibition suppress tumor growth in vitro and in vivo. Future studies are needed to determine whether RANKL is important for the malignant transformation and the transition from GCNIS to invasive tumors.

2022-04-19 | GSE197389 | GEO

Effect of RANKL inhibition on fibrous dysplasia lesions (mouse)

Project description:we investigated mechanisms underlying RANKL inhibition with the monoclonal antibody denosumab on FD tissue, and its likely indirect effects on osteoprogenitors, by evaluating human FD tissue pre and post-treatment and in murine in vivo pre-clinical models. Results from this study demonstrate that, beyond its expected anti-osteoclastic effects, denosumab reduces FD lesion activity by decreasing FD cell proliferation and increasing osteogenic maturation, leading to increased bone formation within lesions

2024-01-15 | GSE250356 | GEO

Effect of RANKL inhibition on fibrous dysplasia lesions (human)

Project description:we investigated mechanisms underlying RANKL inhibition with the monoclonal antibody denosumab on FD tissue, and its likely indirect effects on osteoprogenitors, by evaluating human FD tissue pre and post-treatment and in murine in vivo pre-clinical models.Results from this study demonstrate that, beyond its expected anti-osteoclastic effects, denosumab reduces FD lesion activity by decreasing FD cell proliferation and increasing osteogenic maturation, leading to increased bone formation within lesions

2024-01-15 | GSE250355 | GEO

Recombinant RANKL causes modulation of inflammatory signaling pathways in C2C12 myotubes

Project description:Previous reports indicate that RANKL-RANK signaling participates in regulating muscle mass and strength in denervated animals, while RANKL inhibition by OPG-Fc peptide improves the muscle phenotype in dystrophic mdx mice. RANKL has also been shown to activate STAT3 to regulate osteoclastogenesis, although it is not known whether such interaction also plays a role in skeletal muscle. The objective of this aim is to clarify whether RANKL directly affects skeletal muscle.

2022-03-30 | GSE149606 | GEO

Recombinant RANKL causes modulation of inflammatory signaling pathways in C2C12 myotubes

Project description:Recombinant RANKL causes modulation of inflammatory signaling pathways in C2C12 myotubes

| PRJNA629356 | ENA

Gene expression profile of murine intestinal epithelial cells after RANKL treatment

Project description:RANKL (receptor acrivator of NFkB ligand) is a member of TNF superfamily cytokines. In the gastrointestinal tract, RANKL is expressed in the stromal cells of Peyer's patches, and involved in the development of the specialized intestinal epithelial cells, called M cells. To identify the genes involved in M-cell development, we treated BALB/c mice with recombinant GST-RANKL. After RANKL-treatment, epithelial cells were isolated from small intestine, and used for microarray analysis. Total of 15 samples were analyzed. We generated the Excel sheet for comparing gene expression.

2012-06-16 | E-GEOD-37861 | biostudies-arrayexpress

Gene expression profile of murine intestinal epithelial cells after RANKL treatment

2012-06-17 | GSE37861 | GEO

RANK is an independent biomarker of poor prognosis in estrogen receptor-negative breast cancer and functionally contributes to increase tumor aggressiveness

Project description:Analyses of genes expression in estrogen receptor negative, RANK positive, breast cancer orthoxenografts after in vivo treatment (4 weeks) with RANKL , RANK-Fc or denosumab.

2023-01-19 | GSE185513 | GEO

Genome-wide expression profiling in bone marrow-derived macrophage (BMM) cells upon RANKL treatment

Project description:To screen for altered gene expression during osteoclastogenesis, RANKL-treated BMM cells were subjected to gene expression profiling. BMM cells were treated with M-CSF and RANKL for 0, 1, 2 and 3 days. Total RNA was isolated and analyzed by gene expression microarray using the MouseRef-8 v2.0 Expression BeadChip.

2014-07-30 | E-GEOD-57468 | biostudies-arrayexpress

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