Propranolol reduces sarcoma growth and enhances the response to anti-CTLA4 checkpoint inhibitor therapy by modulating the tumor microenvironment
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ABSTRACT:
PROVIDER: PRJNA730885 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR14578894_1.fastq.gz | Fastqsanger.gz | |||
| SRR14578894_2.fastq.gz | Fastqsanger.gz | |||
| SRR14578895_1.fastq.gz | Fastqsanger.gz | |||
| SRR14578895_2.fastq.gz | Fastqsanger.gz | |||
| SRR14578896_1.fastq.gz | Fastqsanger.gz |
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Project description:The nonselective beta blocker, propranolol, which for decades has been used for treatment of cardiovascular conditions, has recently been used successfully to treat metastatic angiosarcoma. These results have led to an orphan drug designation by the European Medicines Agency for the treatment of soft tissue sarcomas. The anti-tumor effects of propranolol are suggested to involve the reduction of cancer cell proliferation as well as angiogenesis. Here, we have investigated the anti-angiogenic properties of propranolol in the context of stimulating an anti-tumor immune response. We show that oral administration of propranolol delays tumor progression of MCA205 fibrosarcoma tumors and improves the survival rate of tumor bearing mice. Propranolol works by reducing tumor angiogenesis and facilitating an anti-tumoral microenvironment with increased T cell infiltration and reduced infiltration of myeloid-derived suppressor cells (MDSCs). Using T cell deficient mice, we demonstrate that the full anti-tumor effect of propranolol requires the presence of T cells. Flow cytometry-based analysis and RNA sequencing of FACS-sorted cells show that propranolol-treatment leads to an upregulation of PD-L1 on tumor-associated macrophages (TAMs) and changes in their chemokine expression profile. Lastly, we observe that the efficacy of anti-CTLA4 therapy is significantly enhanced by the co-administration of propranolol. Our results identify propranolol as an immune modulating agent, which can improve immune checkpoint inhibitor therapies in soft tissue sarcoma patients and potentially also in other cancers.
2022-03-01 | GSE174645 | GEO
Project description:We demonstrate that the β-blocker propranolol strongly reduces lung metastasis in multiple murine models, with the reduction being completely dependent on CD4+ T cells. To dissect the underlying mechanisms behind the anti-metastatic effect of propranolol, an experimental B16F10 lung metastasis model was combined with propranolol treatment. Total lung RNA or RNA from FACS-isolated lung monocytes and magnetic bead-isolated CD4+ T-cells were subjected to RNA sequencing.
2025-09-17 | GSE275763 | GEO
Project description:The lipopolysaccharide-responsive beige-like anchor protein (LRBA) deficiency causes severe autoimmune diseases and cytotoxic T-lymphocyte-associated protein 4 (CTLA4) loss in humans. However, the impact of LRBA on antitumor immunity remains understudied. Here, we identified the role of LRBA in antitumor immunity and developed a novel immunotherapy for cancers. Interestingly, LRBA was negatively associated with antitumor immunity in human patients. Using high-throughput screening and subsequent structure-based hit optimization, we discovered a small molecule LC427 that bound directly to LRBA, and selectively interfered with the LRBA-CTLA4 interaction. This mechanistically unique LC427 facilitated the lysosomal degradation of CTLA4, and bolstered survival and functions of activated T cells. Importantly, orally administrated LC427 increased tumor-infiltrating CD8+ T cells and displayed effective antitumor activity in tumor-bearing mouse models. Notably, LC427 did not induce typical irAEs observed with immune checkpoint inhibitors in colitis models. Our study demonstrates that targeting LRBA offers a novel and effective strategy with a favorable safety profile, highlighting the potential of LRBA-based immunomodulatory therapies in the treatment of cancers.
2026-01-23 | PXD064363 | Pride
Project description:Recently, targeting or reinvigorating exhausted T cells have become the focus of cancer immunotherapy. Propranolol, a non-selection β1 and β2 adrenergic receptor blocker, or in combination with other drug, can inhibit the development of various tumors. Additionally, β2-adrenergic receptor (ADRB2) signaling suppresses the effector function of CD8+ T cell. However, whether propranolol plays an anti-tumor role by directly inhibiting T cell exhaustion remains unclear. In this study, we found that Propranolol significantly inhibited the development of AOM/DSS-induced colorectal cancer, and reduced the exhaustion of infiltrating T cell in colorectal cancer tissues. The anti-tumor effect of propranolol was further determined by CT26, B16F10, and MC38 subcutaneous tumor models in vivo. Cell viability analysis showed that Propranolol concentration below 40 μM had no effect on the viability of CT26 colorectal cancer cells. We also found that propranolol treatment did not inhibit the growth of tumors in BALB/c nude mice. The above results indicated that Propranolol relied on T cells to exert its anti-tumor effects. Bioinformatics analysis highlighted that ADRB2 was positive correlated with T cell exhaustion signature in colon adenocarcinoma, pancreatic adenocarcinoma, testicular germ cell tumors, and glioblastoma multiforme patients using the website of GEPIA. Accordingly, Propranolol directly inhibited T cells exhaustion, and increased IFN-γ secretion of CD4+ and CD8+ T cells in vitro. Collectively, propranolol plays anti-tumor role by directly inhibiting T cell exhaustion.
2023-04-28 | GSE209807 | GEO
Project description:We established a rat model of myocardial Infarction by performing a surgical operation of left anterior descending coronary artery occlusion under sterie conditions. Wistar rats were previously randomly divided into 4 groups: control, ischemia, ischemia-propranolol, and non-ischemia-propranolol. Our data suggested that propranolol could reverse many microRNAs with too high or too low expression in the ischemia group versus control group.
2009-11-19 | GSE18129 | GEO
Project description:Propranolol is a widely used beta blocker that consists of a racemic mixture of R and S stereoisomers. Only the S stereoisomer has significant activity against the beta-adrenergic receptor. A fortuitous clinical observation was made in an infant who received propranolol for cardiac disease, and regression of a hemangioma of infancy was noted. order to gain further insights in the mechanisms of action of R-propranolol in vivo, we subjected vehicle- and R-propranolol-treated tumors to RNAseq analysis. Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis showed that choline metabolism was the pathway most affected by R-propranolol treatment. Consistent with this, the most highly regulated gene by R-propranolol treatment was Betaine-Homocysteine Methyl Transferase (Bhmt). Other genes that are involved in tumor suppressive activities such as Early Growth Response 1 (Egr1) and AP-1 subunit, which are both transcription factors implicated in tumor suppression. Egr1 regulates important tumor suppressors such as PTEN and p53, and upregulates tumor necrosis factor α (TNF-α). Fos, which has been known to be rearranged and expressed frequently in epithelioid hemangioma, was also upregulated in R-propranolol-treated samples. The genes identified in the RNAseq analysis pose as interesting targets for further investigations.
2019-10-04 | GSE138403 | GEO
Project description:We established a rat model of myocardial Infarction by performing a surgical operation of left anterior descending coronary artery occlusion under sterie conditions. Wistar rats were previously randomly divided into 4 groups: control, ischemia, ischemia-propranolol, and non-ischemia-propranolol. Our data suggested that propranolol could reverse many microRNAs with too high or too low expression in the ischemia group versus control group. Wistar rats were initially anesthetized with pentobarbital (40 mg/kg, i.v.), which were previously randomly divided into 4 groups: control, ischemia (MI), ischemia-propranolol (MI-PRO), and non-ischemia-propranolol (NMI-PRO). The rat model of MI was established by performing a surgical operation of left anterior descending coronary artery occlusion under sterie conditions. Successful occlusion was confirmed by an increase in the amplitude of R wave of lead I during the first few seconds of each occlusion and elevation of S-T segment of lead II, and a 20-30% decline in the arterial blood pressure compared to the pre-ischemic values mesured by a previously installed ECG recorder (BL 420, ChengDu TME Technology Co, Ltd, ChengDu, China). Propranolol was administrated 2 months before the experiment with daily oral doses of 50 mg/kg. Hearts were quickly isolated after the rats were sacrificed and the ischemic zone of the left ventricle was prepared for the miRNA microarray experiment. Control and NMI-PRO animals underwent open chest procedures without coronary artery occlusion.
2010-06-19 | E-GEOD-18129 | biostudies-arrayexpress
Project description:We investigated the effect of a daily propranolol treatment (0.5mg/mL in the water bottle) on human melanoma xenografts development and the subsequent transcriptomic variations
2014-05-30 | E-MTAB-2404 | biostudies-arrayexpress
Project description:We investigated the effect of a daily propranolol treatment (0.5mg/mL in the water bottle) on human melanoma xenografts development and the subsequent transcriptomic variations
2014-05-30 | E-MTAB-2405 | biostudies-arrayexpress
Project description:Acquired resistance to the BRAF inhibitor vemurafenib remains a major obstacle in melanoma therapy. Drug repurposing offers a promising strategy to overcome such resistance. Here, we investigated the β-blocker propranolol as a sensitizer to vemurafenib in resistant melanoma. Using vemurafenib-resistant cell lines (A375-VR and patient-derived P-8-VR), we found that propranolol restored vemurafenib sensitivity both in vitro and in vivo. RNA sequencing revealed that propranolol significantly upregulated CDK11A and CDK11B. Functional studies demonstrated that knockdown of CDK11 attenuated the pro-apoptotic and cell cycle arrest effects of propranolol and vemurafenib. Mechanistically, propranolol induced G1/S phase arrest and apoptosis without affecting MAPK or AKT pathway reactivation. In a xenograft model, the combination of propranolol and vemurafenib significantly suppressed tumor growth and improved survival. Our study identifies CDK11 upregulation as a novel mechanism by which propranolol reverses vemurafenib resistance, supporting the clinical potential of this drug combination in resistant melanoma.
2026-01-19 | GSE316499 | GEO