Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Inhibition of circulating glycocholic acid-regulated signaling potentiates immune checkpoint therapy in colorectal cancer

ABSTRACT: Serum bile acids (BAs) are an important risk factor for the initiation and progression of cancer, but their roles in colorectal cancer (CRC) remain largely unknown. The present study showed that glycocholic acid (GCA), a primary BA, was highly accumulated in the serum of patients with CRC. In a mouse model of CRC, GCA diet promoted programmed death-ligand 1 (PD-L1) expression in tumors, which attenuated CD8+ T cell-mediated antitumor responses in the tumor microenvironment (TME), and promoted the occurrence and development of CRC. Increased PD-L1 expression was caused by the reduction in activity of the BA receptor farnesoid X receptor (FXR). Mechanistically, FXR acted as transcriptional repressor for the transcription factor SRY-box transcription factor 14 (SOX14), and suppressed the palmitoylation and stabilization of PD-L1 by inhibiting the SOX14-mediated expression of zinc finger DHHC-type palmitoyl transferase 9 (DHHC9). Notably, genetically silencing SOX14 and DHHC9 in cancer cells or administering an FXR agonist synergized with anti-PD-1 therapy, leading to reduced tumor growth in GCA-fed mice. Together, the present findings reveal a previously unrecognized mechanism of BA in remodeling the TME to mediate CRC resistance to immunotherapy, which may have clinical implications for developing immunotherapy strategies for patients with CRC.

ORGANISM(S): Homo sapiens

PROVIDER: GSE241076 | GEO | 2024/08/17

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

Exercise inhibits tumor progression and improves the therapeutic efficacy of PD-1 blockade in colorectal cancer preclinical models

Project description:Exercise training (ExT) has shown antitumor effects in many preclinical cancer models. In the present study, we utilize MC38 and CT26 cells, which represent MSI and MSS colorectal carcinomas respectively, to study the effects and mechanisms of ExT alone or in combination with PD-1 based immunotherapy. Using treadmill running and PD-1/PD-L1 blockade, we demonstrated that post-implant exercise training has broad anticancer activities in murine models of CRC. Specifically, in MSI CRC models, ExT induces beneficial metabolic and immunological adaptations, leading to a more significant inhibition in tumors treated with PD-1/PD-L1 blockade, suggesting a genotype-directed combinatory therapy for the subgroup of CRC patients. Moreover, ExT might be a safe and alternative anticancer strategy for cancers resistant to the PD-1 based immunotherapy, such as patients with MSS CRC tumors.

2021-04-16 | GSE172162 | GEO

Phagocytes as Trojan horse for Fusobacterium nucleatum routing to the tumor tissues and enhance tumor metastasis

Project description:The facultative intracellular bacterium Fusobacterium nucleatum (Fn), mediates tumorigenesis and progression in CRC. However, the origin of intracellular Fn and the role of Fn-infected phagocytes in tumor microenvironment remains unclear. Here, we observed Fn-infected neutrophils/macrophages (PMNs/MΦ) is accumulated in CRC tumor tissues. Fn can survive inside of PMNs by reducing intracellular ROS levels. The lysozyme inhibitor Fn-MliC induced the expression of the CX3CR1 which suppressed apoptosis of phagocytes. Fn-infected phagocytes can transfer Fn to tumor cells, and Fn-infected CRC cells recruited PMNs and MΦ/monocytes through the CXCL2/8-CXCR2 and CCL5/CCR5 axis. Intracellular Fn upregulated PD-L1 expression through activating NF-κB/STAT3 pathway in PMNs. PD-L1+ PMNs infiltration promotes CRC metastasis and weaken the efficacy of immunotherapy, and eradication intracellular Fn infection retarded the Fn promoted tumor progressing in mice. These results suggest that Fn volved efficient strategies to exploit phagocytes to home to tumor tissues, inhibited immune responses and facilitate tumor metastasis.

2024-01-01 | GSE243383 | GEO

ID3 Enhances PD-L1 Expression by Restructuring MYC and Promotes Colorectal Cancer Immune Evasion [ChIP-seq]

Project description:The inhibitor of DNA-binding protein ID3 is a vital component of immune cells and has been associated with the progression of colorectal cancer (CRC). Despite its significance, its specific role in the immune evasion strategies utilized by CRC remains unclear. RNA-seq analysis revealed that ID3 is associated with the PD-L1 immune checkpoint. We further demonstrated that ID3 modulates PD-L1 expression, suppresses the infiltration and activation of CD8+ T cells, and facilitates the immune escape of CRC cells. Additionally, we found that the knockdown of ID3 significantly enhanced the effectiveness of PD-L1 antibody treatment in combating CRC, reduced the upregulation of PD-L1 induced by the antibody, and altered the immune microenvironment within CRC. Mechanistically, our biological and structural analyses demonstrated that ID3 reconstructed the four-dimensional structure of MYC, thereby enhancing its binding affinity to the PD-L1 promoter and augmenting PD-L1 transcriptional activity. By integrating analysis of ChIP-seq, RNA-seq, and ImmPort gene sets, we found that ID3's DNA-assisted binding function was widespread and could either enhance or suppress gene transcription, not only affecting tumor immune escape through immune checkpoints, but also regulating various cytokines and immune cells involved in tumor immunity. In conclusion, our study uncovered a new mechanism by which ID3 promotes immune evasion in CRC and targeting ID3 may improve the efficacy of anti-PD-1/PD-L1 immunotherapy.

2024-09-30 | GSE275455 | GEO

ID3 Enhances PD-L1 Expression by Restructuring MYC and Promotes Colorectal Cancer Immune Evasion [RNA-seq]

2024-09-30 | GSE275454 | GEO

Evading immune evasion via reprograming of the tumor microenvironment by radiotherapy and simultaneous targeting of TGF-β/PD-L1

Project description:Tumor immunogenicity enhanced by radiotherapy (RT), is often counterbalanced by immune evasive mechanisms and tissue remodeling effects via upregulation of transforming growth factor-β (TGF-β) and programmed cell death-ligand 1 (PD-L1). We report that bintrafusp alfa (BA), a bifunctional fusion protein that simultaneously inhibits TGF-β and PD-L1, is a favorable combination partner for RT in eradicating multiple treatment-resistant tumor models. Beneficial effects of BA+RT (BART) are partly attributed to counterbalancing undesired RT effects and local tumor microenvironment reprograming, leading to reconstitution of tumor immunity and regression of spontaneous lung metastases. Intriguingly, BA, but neither TGF-β trap nor anti–PD-L1 alone, attenuates late-stage RT-induced lung fibrosis. Single cell transcriptome show TGF-β expression is confined to PD-L1+ endothelium and M2/lipofibroblast-like cells. Hence, superior effects of BA could be attributed to its ability to trap TGF-β to relevant PD-L1+ compartments. Here, we provide rationales that BART resensitizes tumors and broadens the therapeutic window.

2021-08-16 | GSE182004 | GEO

Transcriptome analysis of SH-SY5Y neuroblastoma cells treated with copper and copper chelators (Dextran-Catechin - DC, and Tetraethylenepentamine pentahydrochloride - TEPA) in the presence or absence of interferon gamma

Project description:Therapeutic checkpoint antibodies blocking PD1/PD-L1 signaling have radically improved clinical outcomes in cancer. However, the regulation of PD-L1 expression on tumor cells is still poorly understood. Here we show that intra-tumoral copper levels influence PD-L1 expression in cancer cells. Copper supplementation enhanced PD-L1 expression at mRNA and protein levels in cancer cells and RNAseq revealed that copper regulates key signaling pathways mediating PD-L1-driven cancer immune evasion. Conversely, copper chelators inhibited phosphorylation of STAT3 and EGFR and promoted ubiquitin-mediated degradation of PD-L1. Overall, this study reveals an important role for copper in regulating PD-L1 and suggests that anti-cancer immunotherapy might be enhanced by pharmacologically reducing intra-tumor copper levels.

2020-07-28 | GSE155031 | GEO

NFKB2 mediates colorectal cancer cell immune escape and metastasis in a STAT2/PD-L1-dependent manner

Project description:This study systematically analyzed the molecular mechanism and function of nuclear factor kappa B subunit 2 (NFKB2) in colorectal cancer (CRC) to investigate the potential of NFKB2 as a therapeutic target for CRCTo investigate the potential of NFKB2 as a therapeutic target for colorectal cancer (CRC), we conducted a systematic analysis of the molecular mechanism and function of NFKB2 in CRC. VariousA range of experimental techniques, including RNA sequencing, proteome chip assays, and small molecule analysis, were used to obtaingain a deeper understanding of the regulation of NFKB2 in CRC. TheOur results revealed that NFKB2 was upregulated in a significant proportion of patients with advanced hepatic metastasismetastases of CRC. NFKB2 played an importanta role in promoting tumor growth through CD8+ T cell exhaustion. MoreoverAdditionally, NFKB2 directly interacted with signal transducer and activator of transcription 2 (STAT2)STAT2, leading to increased phosphorylation of STAT2 and the upregulation of programmed death ligand 1 (PD-L1)PD-L1 expression. Applying aThe application of a small molecule inhibitor of NFKB2 (Rg5) led to a reduction in PD-L1 expression and improved response to programmed death-1 (PD-1)PD-1 blockade-based immunotherapy. In conclusion,These findings suggest that the facilitated NFKB2-STAT2/PD-L1 axis may suppresses immune surveillance in CRC and targeting NFKB2 maycould enhance the efficacy of immunotherapeutic strategies. Our resultsThis study provides novel insights into the molecular mechanisms underlying the contribution of NFKB2 in CRC immune escape. However, our findings requireand further validation of these findings in a clinical trial is needed to establish NFKB2 inhibition as a therapeutic strategy for CRC patients.

2023-12-21 | GSE250065 | GEO

Immune checkpoint inhibitor monotherapy is sufficient to promote microenvironmental normalization via Type I interferon pathway in PD-L1+ expressing head and neck cancer

Project description:Immune checkpoint blockers (ICBs) targeting programmed death 1(PD-1) are considered effective first-line therapy against PD-1 ligand (PD-L1)-expressing head and neck squamous cell carcinoma (HNSCC). However, associated changes in tumor microenvironment (TME) and mechanisms remain elusive. Oral tumors in C57/BL6 mice were induced by administering 7,12-dimethylbenzanthracene into the buccal mucosa. Single-cell suspension was isolated from tumor tissue; proliferating cells were injected subcutaneously into the left flank of mice to establish Ajou Oral Cancer (AOC) cell lines. Subsequently, a syngeneic PD-L1-expressing HNSCC xenograft model was developed by injecting AOC cells into the buccal or tongue area. The model recapitulated human HNSCC molecular features and showed reliable in vivo tumorigenicity with significant PD-L1 expression. ICB monotherapy induced global changes in TME, including vascular normalization. Furthermore, the anti-tumor effect of ICB monotherapy was superior to those of other therapeutic agents, including cisplatin and anti-vascular endothelial growth factor receptor 2 inhibitors. The ICB-induced anti-tumorigenicity and TME normalization were alleviated by blocking the Type I interferon pathway.In summary, ICB monotherapy is sufficient to induce TME normalization in the syngeneic model; the Type-I interferon pathway is indispensable in realizing ICB effects. Furthermore, these results explain the underlying mechanism of the efficacy of ICB monotherapy against HNSCC expressing PD-L1 in the KEYNOTE-048 trial. This model can assist future research on HNSCC immunotherapy.

2023-12-01 | GSE248271 | GEO

Evading immune evasion via reprograming of the tumor microenvironment by radiotherapy and simultaneous targeting of TGF-β/PD-L1

Project description:Single cell transcriptome showed TGF-β expression is confined to PD-L1+ endothelium and M2 /lipofibroblast-like cells. Hence, superior effects of BA could be attributed to its ability to trap TGF-β to relevant PD-L1+ compartments. Mice were irradiated (photon) and one group of mice was treated with Bintrafusp. Lungs were subsequently dissociated and processed with the 10x genomics 3 prime v2 kit.

2021-08-10 | E-MTAB-10633 | biostudies-arrayexpress

CTLA-4 pathway is instrumental in Giant Cell Arteritis

Project description:BACKGROUND: Giant Cell Arteritis (GCA) causes severe inflammation of the aorta and its branches and is characterized by intense effector T cells infiltration. The roles that immune checkpoints play in pathogenesis of GCA are still unclear.Our aim was to study the immune checkpoints interplay in GCA. METHODS: First, we used VigiBase, the WHO international pharmacovigilance database, to evaluate the relationship between GCA occurrence and immune checkpoint inhibitors (ICI) treatments. We then further dissected the role of ICI in the pathogenesis of GCA, using immunohistochemistry, immunofluorescence, transcriptomics and flow cytometry on peripheral blood mononuclear cells (PBMCs) and aortic tissues of GCA patients and appropriated controls. RESULTS: Using VigiBase, we identified GCA as a significant immune related adverse event associated with anti-CTLA-4 (Cytotoxic T-lymphocyte-associated-protein-4) but not anti-PD-1/PD-L1 treatment. We further dissected a critical role for CTLA-4 pathway in GCA by identification of the dysregulation of CTLA-4-derived gene pathways and proteins in CD4+ T cells (and specifically Tregs) present in blood and aorta of GCA patients versus controls. While Tregs were less abundant and activated/suppressive in blood and aorta of GCA versus controls, they still specifically upregulated CTLA-4. Activated and proliferating CTLA-4+ Ki-67+ Tregs from GCA were more sensitive to anti-CTLA-4 (Ipilimumab)-mediated in vitro depletion versus controls. CONCLUSIONS: We highlighted the instrumental role of CTLA-4 immune checkpoint in GCA which provides a strong rationale for targeting this pathway.

2023-07-03 | GSE236367 | GEO

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data