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Propranolol reduces sarcoma growth and enhances the response to anti-CTLA4 checkpoint inhibitor therapy by modulating the tumor microenvironment

ABSTRACT: Propranolol reduces sarcoma growth and enhances the response to anti-CTLA4 checkpoint inhibitor therapy by modulating the tumor microenvironment

PROVIDER: PRJNA730885 | ENA |

REPOSITORIES: ENA

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Propranolol reduces sarcoma growth and enhances the response to anti-CTLA4 checkpoint inhibitor therapy by modulating the tumor microenvironment

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

Early Changes In B Cell Subsets Predict Risk Of Autoimmunity Following Combination Immune Checkpoint Blockade

Project description:We report changes in B cells in patients treated with combination immune checkpoint blockade (CCB; anti-CTLA4 and anti-PD1)

2017-11-29 | GSE104600 | GEO

Radiation and Dual Checkpoint Blockade Activates Non-Redundant Mechanisms in Cancer

Project description:Response to immune checkpoint inhibitors may be improved through combinations with each other and other therapies, raising questions about non-redundancy and resistance. We report results from parallel studies of melanoma patients and mice treated with anti-CTLA4 and radiation (RT). Although combined treatment improved responses, resistance was common. Computational analyses of immune and transcriptomic profiles (provided here) revealed that resistance in mice was due to upregulation of tumor PD-L1 that drives T cell exhaustion. Accordingly, optimal response requires RT, anti-CTLA4, and anti-PD-L1. Anti-CTLA4 inhibits Tregs, RT diversifies and shapes the TCR repertoire, and anti-PD-L1 reinvigorates exhausted T cells. Together, all three therapies promote the expansion of clonotypes with distinct TCR traits. Similar to mice, patients with melanoma showing high PD-L1 did not respond to RT + anti-CTLA4, demonstrated persistent T cell exhaustion, and rapidly progressed. Thus, the combination of RT, anti-CTLA4, and anti-PD-L1 promotes response through distinct mechanisms.

2015-03-16 | GSE65503 | GEO

Molecular portraits of tumor mutational and micro-environmental sculpting by immune checkpoint blockade therapy

Project description:Immune checkpoint blockade (ICB) has demonstrated significant promise for the treatment of advanced malignancies. Anti-CTLA4 and ant-PD1 therapy can activate the immune system and result in durable control in diseases such as melanoma and non-small cell lung cancer.

2018-01-23 | GSE91061 | GEO

Identifying genomic predictors of sensitivity to immune checkpoint therapy in mouse models of TNBC

Project description:We created new mouse mammary tumor models to identify biomarkers of sensitivity to immune checkpoint inhibitors. Using these models in a syngeneic transplant system and treating with anti-PD1/anti-CTLA4 combination therapy, we profiled treated and non-treated tumors by RNA-SEQ. Herein, the profiled tumors represent models that are resistant or senstitive to immune checkpoint inhibitors at distinct timepoints of therapy and tumor progression.

2019-11-13 | GSE124821 | GEO

Tafazzin Regulates Cell State by Modulating Phosphatidylethanolamine and Phosphatidylserine levels

Project description:Inhibiting tafazzin a cardiolipin remodeling enzyme reduces stemness of AML by modulating the level of phosphatidylserine

2019-03-28 | GSE107045 | GEO

Proteasome regulator PSME4 reduces cellular inflammation and promotes an immunosuppressive tumor microenvironment

Project description:We observed that proteasome regulator PSME4 inhibits antigen presentation and reduces cellular inflammation in lung adenocarcinoma. As tumor inflammation and antigenicity are key to anti-tumor immunity, we examined the effect of PSME4 in vivo by injecting mice with either KP1.9 or KP1.9PSME4_KD lung adenocarcinoma. We analyzed the changes in the immune milieu by performing single cell RNA sequencing (sc-RNA seq) of CD45+ cells, 3 weeks following injection of tumor cells. This allowed us to examine the effect of PSME4 on the early immune response to the tumor.

2023-03-04 | E-MTAB-10745 | biostudies-arrayexpress

Immune checkpoint blockade reprograms systemic immune landscape and tumor microenvironment in obesity-associated breast cancer [tumor]

Project description:Immune checkpoint blockade (ICB) has improved outcomes in some cancers. A major limitation of ICB is that a majority of patients fail to respond, which is partly attributable to immunosuppression. Obesity appears to improve immune checkpoint therapies in some cancers but impacts on breast cancer (BC) remain unknown. In obese mice fed an obesogenic or lean controls on a low fat diet, mice are injected with BC cells andtreated with anti-PD-1 or control. Obesity leads to immunosuppression systemically in tumor-free mice that is exacerbated in tumor-bearing mice. Obesity augments tumor incidence and progression. Anti-PD-1 induces regression in lean mice and potently abrogates progression in obese mice. Anti PD-1 significantly reduces immunosuppressive cells and elevates anti-tumor immune cells. Lamb2, downregulated by anti-PD1, significantly predict patient survival. Last, we identify a microbial signature associated with anti-PD-1 efficacy. In sum, anti-PD-1 is highly efficacious in obese mice by reinvigorating durable antitumor immunity.

2021-05-08 | GSE174053 | GEO

Immune checkpoint blockade reprograms systemic immune landscape and tumor microenvironment in obesity-associated breast cancer [Mammary fat pad, MFP]

2021-05-08 | GSE174044 | GEO

Gene expression profiles of melanoma tumor samples from patients treated with checkpoint inhibitors (mouse)

Project description:Checkpoint inhibitors have improved outcomes for patients with metastatic melanoma, but primary or acquired resistance often occurs. We used the mouse melanoma cell line B16, originally derived from C57BL6 mice, to model changes in tumor cell gene expression that occur with acquired resistance to checkpoint inhibitors. B16 cells used were engineered to express the fluorescent marker tdTomato, to assist monitoring and cell sorting. Previously-untreated B16 cells (F0) were inoculated into C57BL6 mice, followed by treatment with triple-checkpoint inhibitor therapy (3I) with combined antibodies to CTLA4, PD-1, and PD-L1. Tumors that emerged despite immune selection pressure were harvested, grown again in vitro as a cell line, and then re-inoculated into a new generation of mice. This was repeated for 4 generations (F4) until inoculations were 100% successful at generating immune-resistant tumors.

2020-11-01 | GSE122221 | GEO

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