Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1216073 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR32135823_1.fastq.gz | Fastqsanger.gz | |||
| SRR32135823_2.fastq.gz | Fastqsanger.gz | |||
| SRR32135824_1.fastq.gz | Fastqsanger.gz | |||
| SRR32135824_2.fastq.gz | Fastqsanger.gz | |||
| SRR32135825_1.fastq.gz | Fastqsanger.gz |
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Project description:Immune checkpoint inhibitors (ICI), epitomized by PD-1/PD-L1 antibodies, have ushered in a new era in lung cancer treatment. However, ICI monotherapy is only applicable to a small subset of patients with high PD-L1 expression, while most patients with low expression require combination therapies. In this study, we found that β-elemene promotes M1 polarization of tumor-associated macrophages (TAM) and enhances the efficacy of PD-L1 antibody (aPD-L1) in C57BL/6 mice. RNA sequencing and surface plasmon resonance revealed that β-elemene directly binds to FLT1 and inhibits the PI3K/AKT/FOXO1 signaling pathway, thereby mediating TAM M1 polarization. Using FLT1 knockout mice, we further validated the critical role of FLT1 in TAM polarization and confirmed that M1 polarization synergizes with aPD-L1 treatment. Furthermore, co-immunoprecipitation demonstrated that the intracellular domain of FLT1 interacts with and phosphorylates the p85α subunit, initiating downstream signaling cascades. These findings elucidate the synergistic mechanism between β-elemene and aPD-L1. Importantly, as both agents are already clinically approved, we plan to conduct a clinical trial to evaluate the efficacy and safety of this combination therapy.
2026-01-24 | GSE317011 | GEO
Project description:Macrophages form a primary immune cells population in tumor tissues and malignant ascites microenvironment (MAM). They can be activated and polarized into tumor-associated macrophages (TAM) by the embedded environment and promote tumor progression and metastasis However, the molecular mechanisms of MAM in macrophage polarization and the effects on epithelial ovarian cancer (EOC) metastatic progression remain elusive. Here, we found that that MAM modulates RhoA-GTPase-F-actin-Hippo signaling cascade in facilitating M2-like macrophage polarization that, in turn, promotes tumor dissemination. PUFA enriched magligant ascites microenvironment promote macrophage lipid oxidative phosphorylation and supression RhoA-GTPase-Yap1 axis. Genetic ablation Yap1 in macrophage exhibited M2-like polarization and enhanced ovrian tumor dissemination. Pharmacology inhibit Mst1/2 could rescue M2-like TAM polarization in MAM and alter the lipid oxidation of macrophages in MAM, more importantly, inhibit ovarian metastatic properties. Through comparasion primary TAM (P-TAM) and metastasis TAM (M-TAM), we proved that Hippo-Yap1 siganl results M-TAM with high M2/M1 ratio. These findings implicate critical functions of PUFA modulate RhoA-Hippo axis in facility TAM polarization and also suggest manipulation of PUFA metabolism or RhoA-Hippo siganl as a therapeutic strategy aganist EOC metastasis.
2024-05-01 | GSE175552 | GEO
Project description:Programmed death-ligand 1 (PD-L1) is predominantly expressed in the antigen-presenting cells (APCs) that are originated and abundant in bone marrow. The roles of PD-L1 in bone cell differentiation and cancer bone metastasis remain unclear. Here we show that PD-L1 antibody or PD-L1 conditional knockout in the hematopoietic or myeloid lineage suppresses osteoclast differentiation in vitro and in vivo. Bone metastases of breast cancer and melanoma are diminished by PD-L1 antibody or PD-L1 deletion in the myeloid lineage. Transcriptional profiling of bone marrow cells reveals that PD-L1 deletion in the myeloid cells up-regulates immune stimulatory genes, leading to increased macrophage M1 polarization, decreased M2 polarization, enhanced IFN? signaling, and elevated T cell recruitment and activation. All these alterations result in heightened anti-tumor immunity in the cancer microenvironment. Our findings support PD-L1 antibody as a potent therapy for bone metastasis of breast cancer and melanoma by simultaneously suppressing osteoclast and enhancing immunity.
2022-03-07 | GSE190715 | GEO
Project description:The intrinsic regulation of PD-L1 expression remains unclear. Here we report that ZNF652 is a potent transcription repressor of PD-L1. ZNF652 frequently loses heterozygosity (LOH) in various cancers. Higher LOH rate and lack of estrogen-inducible transcription lead to suppressed expression of ZNF652 in triple-negative breast cancer (TNBC). Mechanistically, ZNF652 is physically associated with the NuRD transcription corepressor complex to repress a cohort of genes, including PD-L1. Overexpression of ZNF652 inhibits PD-L1 transcription, whereas depletion of ZNF652 upregulates PD-L1. Loss of ZNF652 in TNBC unleashes PD-L1-mediated immune evasion both in vitro and in vivo. Significantly, ZNF652 expression is progressively lost during breast cancer progression, and low ZNF652 level is correlated with elevated PD-L1 expression, less infiltrated CD8+ T cells, and poor prognosis in TNBC. Our study provides novel insights into PD-L1 regulation, and supports the pursuit of ZNF652 as a potential biomarker and drug target for breast cancer immunotherapy.
2023-09-29 | PXD045945 |
Project description:Anti-PD-L1-based combination immunotherapy has become the first-line treatment for unresectable hepatocellular carcinoma (HCC). However, the objective response rate is lower than 40%, highlighting the need to identify mechanisms of tolerance to immune checkpoint inhibitors and accurate biomarkers of response. Here, we employed next-generation sequencing to analyze HCC samples from 10 patients receiving anti-PD-L1 therapy. Activation of the renin-angiotensin system was elevated in nonresponders compared with responders, and ACE2 expression was significantly downregulated in nonresponders. ACE2 deficiency promoted HCC development and anti-PD-L1 resistance, whereas ACE2 overexpression inhibited HCC progression in immune competent mice. Mass cytometry by time of flight (CyTOF) revealed that ACE2 deficient murine orthotopic tumor tissues featured elevated M2-like tumor-associated macrophages (TAMs), displayed a CCR5+PD-L1+ immunosuppressive phenotype, and exhibited high VEGFα expression. ACE2 downregulated tumor intrinsic CCL5 expression by suppressing NF-κB signaling through the ACE2/angiotensin-(1–7)/Mas receptor axis. The lower CCL5 levels led to reduced activation of the JAK-STAT3 pathway and suppressed PD-L1 and VEGFα expression in macrophages, blocking macrophage infiltration and M2-like polarization. Pharmacological targeting of CCR5 using maraviroc enhanced the tumor suppressive effect of anti-PD-L1 therapy. Together, these findings suggest that activation of the ACE2 axis overcomes the immunosuppressive microenvironment of HCC and may serve as an immunotherapeutic target and predictive biomarker of response to PD-L1 blockade.
2024-10-14 | GSE279110 | GEO
Project description:Anti-PD-L1-based combination immunotherapy has become the first-line treatment for unresectable hepatocellular carcinoma (HCC). However, the objective response rate is lower than 40%, highlighting the need to identify mechanisms of tolerance to immune checkpoint inhibitors and accurate biomarkers of response. Here, we employed next-generation sequencing to analyze HCC samples from 10 patients receiving anti-PD-L1 therapy. Activation of the renin-angiotensin system was elevated in nonresponders compared with responders, and ACE2 expression was significantly downregulated in nonresponders. ACE2 deficiency promoted HCC development and anti-PD-L1 resistance, whereas ACE2 overexpression inhibited HCC progression in immune competent mice. Mass cytometry by time of flight (CyTOF) revealed that ACE2 deficient murine orthotopic tumor tissues featured elevated M2-like tumor-associated macrophages (TAMs), displayed a CCR5+PD-L1+ immunosuppressive phenotype, and exhibited high VEGFα expression. ACE2 downregulated tumor intrinsic CCL5 expression by suppressing NF-κB signaling through the ACE2/angiotensin-(1–7)/Mas receptor axis. The lower CCL5 levels led to reduced activation of the JAK-STAT3 pathway and suppressed PD-L1 and VEGFα expression in macrophages, blocking macrophage infiltration and M2-like polarization. Pharmacological targeting of CCR5 using maraviroc enhanced the tumor suppressive effect of anti-PD-L1 therapy. Together, these findings suggest that activation of the ACE2 axis overcomes the immunosuppressive microenvironment of HCC and may serve as an immunotherapeutic target and predictive biomarker of response to PD-L1 blockade.
2024-10-14 | GSE279109 | GEO
Project description:Anti-PD-L1-based combination immunotherapy has become the first-line treatment for unresectable hepatocellular carcinoma (HCC). However, the objective response rate is lower than 40%, highlighting the need to identify mechanisms of tolerance to immune checkpoint inhibitors and accurate biomarkers of response. Here, we employed next-generation sequencing to analyze HCC samples from 10 patients receiving anti-PD-L1 therapy. Activation of the renin-angiotensin system was elevated in nonresponders compared with responders, and ACE2 expression was significantly downregulated in nonresponders. ACE2 deficiency promoted HCC development and anti-PD-L1 resistance, whereas ACE2 overexpression inhibited HCC progression in immune competent mice. Mass cytometry by time of flight (CyTOF) revealed that ACE2 deficient murine orthotopic tumor tissues featured elevated M2-like tumor-associated macrophages (TAMs), displayed a CCR5+PD-L1+ immunosuppressive phenotype, and exhibited high VEGFα expression. ACE2 downregulated tumor intrinsic CCL5 expression by suppressing NF-κB signaling through the ACE2/angiotensin-(1–7)/Mas receptor axis. The lower CCL5 levels led to reduced activation of the JAK-STAT3 pathway and suppressed PD-L1 and VEGFα expression in macrophages, blocking macrophage infiltration and M2-like polarization. Pharmacological targeting of CCR5 using maraviroc enhanced the tumor suppressive effect of anti-PD-L1 therapy. Together, these findings suggest that activation of the ACE2 axis overcomes the immunosuppressive microenvironment of HCC and may serve as an immunotherapeutic target and predictive biomarker of response to PD-L1 blockade.
2024-10-22 | GSE279750 | GEO
Project description:Histone citrullination is catalyzed by peptidyl arginine deiminases (PAD) that play a role in gene regulation. However, the clinical significance and molecular mechanisms of histone citrullination and PADs in pancreatic ductal adenocarcinoma (PDAC) remain unclear. This study aimed to investigate the role and potential molecular mechanisms of PADs in PDAC. Histone citrullination was upregulated and strongly associated with PAD2 nuclear expression in human PDAC samples. PAD2 nuclear expression correlated with aggressive tumor characteristics and poor prognosis. PAD2 overexpression increased PDAC cell proliferation, whereas its knockdown had the opposite effect in vitro. PAD2 bound to the promoter regions of PRUNE1 and E2F1, resulting in the activation of their mRNA expression via upregulation of histone citrullination and chromatin accessibility at their promoter regions. PAD2 overexpression enhanced tumorigenicity, and increased PRUNE1 expression and M2 tumor-associated macrophage (M2 TAM) infiltration in subcutaneous and orthotopic PDAC models. In vitro assay showed that macrophages cultured in a conditioned medium from PAD2-expressing PDAC cells exhibited an increase of M2 TAM-related markers in a PRUNE1-dependent manner. Treatment with the PAD2 inhibitors Cl-amidine and AFM-30a selectively impaired the growth and tumorigenicity of PAD2-expressing PDAC cells in vitro and in vivo. Furthermore, the triple-high expression of nuclear PAD2, PRUNE1, and the M2 TAM marker CD206 may serve as independent adverse prognostic factors for human PDAC. Conclusively, PAD2-mediated histone citrullination drives PDAC progression by epigenetically regulating downstream target genes and influencing the tumor microenvironment. The PAD2-PRUNE1-M2 TAM axis may be a promising therapeutic target and prognostic indicator for PDAC.
2025-06-30 | GSE281497 | GEO
Project description:Colorectal cancer often produces an immunosuppressive microenvironment, which prevents them from responding to immunotherapy. Effective treatment options have not been found yet. Here, based on the observation that Lobeline, an alkaloid from the herbal medicine Lobelia Chinensis, inhibited tumor in MC38 colon cancer xenograft mouse model. We performed single-cell transcriptome sequencing analysis of Lobeline and PBS-treated tumors in mice, and found that Lobeline promoted TAM polarization towards M1-like while inhibited its polarization towards M2-like. In addition, Lobeline upregulated the mRNA level of secreted Ly-6/UPAR-related protein 1 (Slurp1) in cancer cells. The inhibitory effect of Lobeline on tumor load and regulation of TAM polarization disappeard in Slurp1-/- mice or WT mice injected with Slurp1 knockdown adenovirus, suggesting that Slurp1 mediates the process of Lobeline regulates TAM polarization and inhibits tumor progression. Through target responsive accessibility profiling (TRAP), isothermal titration calorimetry (ITC) and microcalorimetric mobility shift assay (MST), we demonstrated that MAPK14 was the target protein of Lobeline. At the mechanistic level, upon binding to MAPK14 in colon cancer cells, Lobeline prevented the nuclear translocation of MAPK14, which decreases the level of phosphorylated p53. Subsequently, the negative transcriptional regulation of Slurp1 by p53 was inhibited, that facilitated the transcription and secretion of Slurp1. Furthermore, the combination of Lobeline and PD-1 antibody showed stronger anti-tumor effect. Thus, these findings suggested that the Lobeline-mediated anti-tumor immune activation might be a promising therapeutic strategy for colorectal cancer.
2025-02-13 | GSE247841 | GEO
Project description:Programmed cell death 1 ligand 1 (PD-L1) is known to suppress immune system and to be an unfavorable prognostic factor in ovarian cancer. The purpose of this study was to elucidate the function of PD-L1 in peritoneal dissemination. Tumor cell lysis by CTLs was attenuated when PD-L1 on tumor cells was overexpressed and promoted when it was silenced. PD-L1 overexpression also inhibited gathering and degranulation of CTLs. Gene expression profile of mouse CTLs caused by PD-L1-overexpressing ovarian cancer was related to human CTLs exhaustion. In mouse ovarian cancer dissemination models, depleting PD-L1 expression on tumor cells resulted in inhibited tumor growth in the peritoneal cavity and prolonged survival. Restoring immune function by inhibiting immune-suppressive factors such as PD-L1 may be a promising therapeutic strategy for peritoneal dissemination. Genome-wide transcriptional changes in OT-1 mouse CD8+ T cells that were co-incubated with OVA peptide-loaded ID8 mouse ovarian cancer cell lines. CTLs from 4 mice were devided into 2 groups, and co-incubated with PD-L1-overexpressed ID8 or PD-L1-depleted ID8.
2012-07-09 | E-GEOD-39205 | biostudies-arrayexpress