Similar Datasets
Project description:Denosumab Enhances antitumour Immunity by Suppressing SPP1 and Boosting Cytotoxic T Cells
| PRJNA1118819 | ENA
Project description:The efficacy of stimulator of interferon genes (STING) agonists is compromised by various factors, primarily inefficient intracellular delivery, low/lack of endogenous STING expression in many tumours and a complex balance between tumour control and progression. Here, we report a universal STING mimic (uniSTING) based on a polymeric architecture. The uniSTING activates STING signalling in a range of mouse and human cell types, independent of endogenous STING expression, and selectively stimulates tumour control IRF3/IFN-I pathways, but not tumour progression NF-κB pathways. Intratumoural or systemic injection of uniSTING-mRNA via lipid nanoparticles (LNP) results in potent anti-tumour efficacy across established and advanced metastatic tumour models, including triple negative breast cancer, lung cancer, melanoma and orthotopic/metastatic liver malignancies. Furthermore, uniSTING displays an effective antitumour response superior to 2’3’-cGAMP and ADU-S100. By favouring IRF3/IFN-I activity over the pro-inflammatory NF-κB signalling pathway, uniSTING promotes dendritic cell maturation and antigen specific CD8+ T cell responses. Extracellular vesicles released from uniSTING-treated tumour cells further sensitise dendritic cells via exosome containing miRNAs that reduced the immunosuppressive Wnt2b and a combination of LNP-uniSTING-mRNA with α-Wnt2b antibodies synergistically inhibit tumour growth and prolong animal survival. Collectively, these results demonstrate the LNP-mediated delivery of uniSTING-mRNA as a strategy to overcome the current STING therapeutic barriers, particularly for the treatment of multiple cancer types in which STING is downregulated or absent.
2024-01-24 | GSE253681 | GEO
Project description:The efficacy of stimulator of interferon genes (STING) agonists is compromised by various factors, primarily inefficient intracellular delivery, low/lack of endogenous STING expression in many tumours and a complex balance between tumour control and progression. Here, we report a universal STING mimic (uniSTING) based on a polymeric architecture. The uniSTING activates STING signalling in a range of mouse and human cell types, independent of endogenous STING expression, and selectively stimulates tumour control IRF3/IFN-I pathways, but not tumour progression NF-κB pathways. Intratumoural or systemic injection of uniSTING-mRNA via lipid nanoparticles (LNP) results in potent anti-tumour efficacy across established and advanced metastatic tumour models, including triple negative breast cancer, lung cancer, melanoma and orthotopic/metastatic liver malignancies. Furthermore, uniSTING displays an effective antitumour response superior to 2’3’-cGAMP and ADU-S100. By favouring IRF3/IFN-I activity over the pro-inflammatory NF-κB signalling pathway, uniSTING promotes dendritic cell maturation and antigen specific CD8+ T cell responses. Extracellular vesicles released from uniSTING-treated tumour cells further sensitise dendritic cells via exosome containing miRNAs that reduced the immunosuppressive Wnt2b and a combination of LNP-uniSTING-mRNA with α-Wnt2b antibodies synergistically inhibit tumour growth and prolong animal survival. Collectively, these results demonstrate the LNP-mediated delivery of uniSTING-mRNA as a strategy to overcome the current STING therapeutic barriers, particularly for the treatment of multiple cancer types in which STING is downregulated or absent.
2024-01-22 | GSE253724 | GEO
Project description:Current chemotherapy or immunotherapy regimens for pancreatic cancer are limited. Although minimally invasive irreversible electroporation (IRE) ablation is a promising option for unresectable pancreatic cancers, the typical immunosuppressive tumour microenvironment promotes immune evasion and rapid tumour recurrence. Thus, triggering efficient amplification of endogenous adaptive antitumour immunity is critical for improving immunotherapy after ablation therapy. Here, we developed a hydrogel microsphere vaccine as an immune amplifier for post-ablation cancer immunotherapy. The vaccine acts as a general immune amplifier to trigger a rocket-like amplification of the cDC1-mediated antigen cross-presentation cascade, resulting in dramatic amplification of the antitumour immunity of endogenous CD8+ T cells. We also showed that the hydrogel microsphere vaccine promoted the transformation of pancreatic cancer from "cold" to "hot" tumours in a safe and efficient manner, significantly increased the survival of mice bearing orthotopic pancreatic tumours, and induced strong systemic antitumour immunity, which inhibited the growth of distant metastases.
2023-05-22 | GSE215417 | GEO
Project description:Accumulating evidence suggests that metabolic rewiring in malignant cells supports tumour progression not only by providing cancer cells with increased proliferative potential and an improved ability to adapt to adverse microenvironmental conditions but also by favouring the evasion of natural and therapy-driven antitumour immune responses. Here, we review cancer cell-intrinsic and cancer cell-extrinsic mechanisms through which alterations of metabolism in malignant cells interfere with innate and adaptive immune functions in support of accelerated disease progression. Further, we discuss the potential of targeting such alterations to enhance anticancer immunity for therapeutic purposes.
| S-EPMC11365797 | biostudies-literature
Project description:The microbiome has a significant impact on immune health and response to immune-stimulating treatments, including cancer immunotherapy. However, the molecular mechanisms by which commensal microbes influence cancer immunology remain poorly understood. Here, we report on the discovery of a class of microbiome-derived metabolites called hydroxyphenyl propanoates (HPP) that enhance tumour immune surveillance in mice and synergize with immune checkpoint blockade (ICB) therapy. HPP molecules act as broad spectrum potentiators of innate immune signalling pathways in tumour-associated myeloid cells by promoting cleavage of the pore-forming protein gasdermin D (GSDMD), a critical effector of canonical and non-canonical inflammasome signalling. Heightened secretion of proinflammatory cytokines from HPP-treated myeloid cells, including IL-1β, promotes NF-κB activity within tumour-infiltrating leukocytes. This leads to heightened anticancer CD8 T cell accumulation, tumour regression, and long-term cancer control by immune checkpoint therapy in mice. Human peripheral blood mononuclear cells (PBMCs) respond to HPP treatment in a similar way. GSDMD cleavage also associates with a favourable response to ICB therapy in advanced stage melanoma patients. Taken together, our study uncovers a mechanism of microbiome-mediated modulation of host antitumour immunity that is modifiable and can be harnessed to enhance the efficacy of cancer immunotherapy. The proteomics part involved searching for hydroxuphenyl pyruvate interactors by using thermal profiling. TMT 10 plex and a method utilizing real-time search was used for quantification.
2025-05-06 | PXD045790 | Pride
Project description:The secretory enzyme human ribonuclease 1 (RNase1) is involved in innate immunity and anti-inflammation, achieving host defense and anti-cancer effects; however, whether RNase1 contributes to adaptive immune response in the tumor microenvironment (TME) remains unclear. Here, we established a syngeneic immunocompetent mouse model in breast cancer and demonstrated that ectopic RNase1 expression significantly inhibited tumor progression. Overall changes in immunological profiles in the mouse tumors were analyzed by mass cytometry and showed that the RNase1-expressing tumor cells significantly induced CD4+ Th1 and Th17 cells and natural killer cells and reduced granulocytic myeloid-derived suppressor cells, supporting that RNase1 favors an antitumor TME. Specifically, RNase1 increased expression of T cell activation marker CD69 in a CD4+ T cell subset. Notably, analysis of cancer-killing potential revealed that T cell-mediated antitumor immunity was enhanced by RNase1, which further collaborated with an EGFR-CD3 bispecific antibody to protect against breast cancer cells across molecular subtypes. Our results uncover a tumor-suppressive role of RNase1 through adaptive immune response in breast cancer in vivo and in vitro, providing a potential treatment strategy of combining RNase1 with cancer immunotherapies for immunocompetent patients.
| S-EPMC10321278 | biostudies-literature
Project description:Macrophages are one of the essential components of the tumour microenvironment (TME) of many cancers and show complex heterogeneity and functions. More recent research has been focusing on the characterisation of tumour-associated macrophages (TAMs). Previously, our study demonstrated that caerin 1.1/1.9 peptides significantly improve the therapeutic efficacy of combined specific immunotherapy and immune checkpoint blockade in a murine transplantable tumour model (TC-1). In this study, the mice inoculated with TC-1 tumour were immunised differently. The TAMs were isolated using flow cytometry and characterised by cytokine ELISA. The survival rates of mice with different treatments containing caerin 1.1/19 were assessed comparatively, including those with/without macrophage depletion. The single-cell RNA sequencing (scRNA-seq) data of previous studies were integrated to further reveal the functions of TAMs with the treatments containing caerin 1.1/1.9. As a comparison, the TAMs of stage I and II cervical cancer patients were analysed using scRNA-seq analysis. We demonstrate that caerin induced tumour clearance is associated with infiltration of tumours by IL-12 secreting Ly6C+F4/80+ macrophages exhibiting enhanced IFN-α response signalling, renders animals resistant to further tumour challenge, which is lost after macrophage depletion. Our results indicate that caerin 1.1/1.9 treatment has great potential in improving current immunotherapy efficacy.
| S-EPMC9738106 | biostudies-literature
Project description:Dendritic cell- (DC-) based vaccination has emerged as a promising antitumour immunotherapy. However, overcoming immune tolerance and immunosuppression in the tumour microenvironment (TME) is still a great challenge. Recent studies have shown that Rose Bengal (RB) can effectively induce immunogenic cell death (ICD) in cancer cells, presenting whole tumour antigens for DC processing and presentation. However, the synergistic antitumour effect of combining intralesional RB with immature DCs (RB-iDCs) remains unclear. In the present study, we investigated whether RB-iDCs have superior antitumour effects compared with either single agent and evaluated the immunological mechanism of RB-iDCs in a murine lung cancer model. The results showed that intralesional RB-iDCs suppressed subcutaneous tumour growth and lung metastasis, which resulted in 100% mouse survival and significantly increased TNF-α production by CD8+ T cells. These effects were closely related to the induction of the expression of distinct ICD hallmarks by RB in both bulk cancer cells and cancer stem cells (CSCs), especially calreticulin (CRT), thus enhancing immune effector cell (i.e., CD4+, CD8+, and memory T cells) infiltration and attenuating the accumulation of immunosuppressive cells (i.e., Tregs, macrophages, and myeloid-derived suppressor cells (MDSCs)) in the TME. This study reveals that the RB-iDC vaccine can synergistically destroy the primary tumour, inhibit distant metastasis, and prevent tumour relapse in a lung cancer mouse model, which provides important preclinical data for the development of a novel combinatorial immunotherapy.
| S-EPMC8824725 | biostudies-literature
Project description:Giant cell granulomas of the jaws often occur sporadically as single central or peripheral lesions. They are characterized by KRAS, FGFR1, or TRPV4 somatic mutations, the latter occurring exclusively in the central form. Less commonly, multiple giant cell lesions can develop in the context of syndromes such as cherubism, which is an autosomal dominant bone disease. Morphologically, giant cell granulomas can closely resemble other giant cell-rich lesions such as non-ossifying fibroma and aneurysmal bone cyst, and to a minor extent giant cell tumour of bone and chondroblastoma. The epigenetic basis of these giant cell-rich tumours is unclear and, recently, DNA methylation profile has been shown to be clinically useful for the diagnosis of other tumour types, including brain tumours as well as bone and soft tissue sarcomas. Therefore, we aimed to assess the DNA methylation profile of central and peripheral sporadic giant cell granulomas of the jaws and cherubism to test whether DNA methylation patterns can help to distinguish these entities. Additionally, we further compared the DNA methylation profile of these lesions with those of other giant cell-rich mimics to investigate if the microscopic similarities extend to the epigenetic level. Our results showed that central and peripheral sporadic giant cell granulomas of the jaws and cherubism share a related DNA methylation pattern with that of peripheral sporadic giant cell granulomas and cherubism appearing slightly distinct, while central sporadic giant cell granulomas show overlap with both of the former. Non-ossifying fibroma, aneurysmal bone cyst, giant cell tumour of bone, and chondroblastoma, on the other hand, have distinct methylation patterns. Therefore, DNA methylation profiling is currently not capable of clearly distinguishing sporadic and cherubism-associated giant cell lesions of the jaws. Conversely, it could discriminate sporadic giant cell granulomas from their giant cell-rich mimics.
2023-10-18 | GSE218252 | GEO