Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Blocking CX3CR1+ Tumor-associated Macrophages Synergize with anti-PD-1 Therapy in Hepatocellular Carcinoma

ABSTRACT: The efficacy of immune checkpoint inhibitors (ICI) in hepatocellular carcinoma (HCC) treatment remains limited, warranting further investigation into the underlying mechanisms. Accumulating evidence indicates that myeloid cells within the tumor microenvironment (TME) play a role in immune evasion and treatment resistance. In this study, we aimed to explore the contribution of tumor-associated macrophages (TAMs) in the HCC TME. Our findings unveil the critical involvement of CX3C motif chemokine receptor 1 (CX3CR1)-positive TAMs in inducing T cell exhaustion through interleukin-27 (IL-27) secretion, providing valuable insights into the mechanisms underlying the suboptimal efficacy of anti-PD-1 therapy in HCC. Additionally, we identified prostaglandin E2 (PGE2) released by immune-attacked tumor cells as a key driver of CX3CR1+ TAM recruitment. To enhance the therapeutic response to current anti-PD-1 therapy, we propose a novel treatment strategy that combines targeted depletion of CX3CR1+ TAMs with anti-PD-1 therapy. Overall, our study contributes to the understanding of TAMs' role in cancer immunotherapy and presents potential clinical implications for HCC treatment. By targeting CX3CR1+ TAMs in conjunction with anti-PD-1 therapy, we have the potential to enhance the effectiveness of immunotherapeutic interventions in HCC patients.

ORGANISM(S): Mus musculus

PROVIDER: GSE263240 | GEO | 2024/07/25

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

S100A9 from tumor-associated macrophage enhances cancer stem cell-like properties of hepatocellular carcinoma

Project description:Tumor-associated macrophages (TAMs) are crucial components of the tumor microenvironment (TME). They play vital roles in hepatocellular carcinoma (HCC) progression. However, the interactions between TAMs and HCC cells have not been fully characterized. In this study, TAMs were induced using human monocytic cell line THP-1 cells in vitro to investigate their functions in HCC progression. S100 calcium binding protein A9 (S100A9), an inflammatory microenvironment-related secreted protein, was identified to be significantly upregulated in TAMs. S100A9 expression in tumor tissues was associated with poor survival of HCC patients. It could enhance the stem cell-like properties of HepG2 and MHCC-97H cells by activating nuclear factor-kappa B (NF-κB) signaling pathway through advanced glycosylation end-product specific receptor (AGER) in a Ca2+-dependent manner. Furthermore, we found that, after treatment with S100A9, HepG2 and MHCC-97H cells recruited more macrophages via chemokine (C-C Motif) ligand 2 (CCL2), which suggests a positive feedback between TAMs and HCC cells. Taken together, our findings reveal that TAMs could upregulate secreted protein S100A9 and enhance the stem cell-like properties of HCC cells, and provide a potential therapeutic target for combating HCC.

2020-10-23 | GSE158792 | GEO

S100A9 from tumor-associated macrophage enhances cancer stem cell-like properties of hepatocellular carcinoma (RNA-Seq)

Project description:Tumor-associated macrophages (TAMs) are crucial components of the tumor microenvironment (TME). They play vital roles in hepatocellular carcinoma (HCC) progression. However, the interactions between TAMs and HCC cells have not been fully characterized. In this study, TAMs were induced using human monocytic cell line THP-1 cells in vitro to investigate their functions in HCC progression. S100 calcium binding protein A9 (S100A9), an inflammatory microenvironment-related secreted protein, was identified to be significantly upregulated in TAMs. S100A9 expression in tumor tissues was associated with poor survival of HCC patients. It could enhance the stem cell-like properties of HepG2 and MHCC-97H cells by activating nuclear factor-kappa B (NF-κB) signaling pathway through advanced glycosylation end-product specific receptor (AGER) in a Ca2+-dependent manner. Furthermore, we found that, after treatment with S100A9, HepG2 and MHCC-97H cells recruited more macrophages infiltration via chemokine (C-C Motif) ligand 2 (CCL2), which suggests a positive feedback between TAMs and HCC cells. Taken together, our findings reveal that TAMs could upregulate S100A9 and enhance the stem cell-like properties of HCC cells, and provide a potential therapeutic target for combating HCC.

2020-10-23 | GSE159264 | GEO

Targeting the RNA m6A reader YTHDF2 in tumor-associated macrophages shapes tumor immunity and immunotherapy [scRNA-seq]

Project description:The presence of tumor-associated macrophages (TAMs) in the tumor microenvironment (TME) affects cancer progression and immunotherapy response. The RNA m6A methylation, an epigenetic modification, has recently been found to play a pivotal role in shaping the TME. However, the role and underlying mechanisms by which RNA m6A methylation regulates TAMs function and anti-tumor immunity remain elusive. Here we show that depletion of YTHDF2, a well-known m6A reader, in TAMs suppresses tumor growth and metastasis. Myeloid YTHDF2 deficiency reprograms TAMs to anti-tumorigenic type and increases their cross-presentation ability, thereby enhancing CD8+T cell-mediated anti-tumor immunity. Transcriptome-wide screening identifies YTHDF2 deficiency facilitates anti-tumorigenic TAMs reprogramming through targeting IFN-γ-STAT1 signaling. Selectively targeting YTHDF2 in TAMs using toll-like receptor 9 agonist - conjugated small interfering RNA against YTHDF2 effectively promotes anti-tumor immunity, restrains tumor growth, and enhances the efficacy of anti-PD-L1 therapy. Together, our findings suggest that YTHDF2 in TAMs might be a promising therapeutic target for cancer immunotherapy.

2022-08-01 | GSE189193 | GEO

Targeting the RNA m6A reader YTHDF2 in tumor-associated macrophages shapes tumor immunity and immunotherapy

Project description:The presence of tumor-associated macrophages (TAMs) in the tumor microenvironment (TME) affects cancer progression and immunotherapy response. The RNA m6A methylation, an epigenetic modification, has recently been found to play a pivotal role in shaping the TME. However, the role and underlying mechanisms by which RNA m6A methylation regulates TAMs function and anti-tumor immunity remain elusive. Here we show that depletion of YTHDF2, a well-known m6A reader, in TAMs suppresses tumor growth and metastasis. Myeloid YTHDF2 deficiency reprograms TAMs to anti-tumorigenic type and increases their cross-presentation ability, thereby enhancing CD8+T cell-mediated anti-tumor immunity. Transcriptome-wide screening identifies YTHDF2 deficiency facilitates anti-tumorigenic TAMs reprogramming through targeting IFN-γSTAT1 signaling. Selectively targeting YTHDF2 in TAMs using toll-like receptor 9 agonist - conjugated small interfering RNA against YTHDF2 effectively promotes anti-tumor immunity, restrains tumor growth, and enhances the efficacy of anti-PD-L1 therapy. Together, our findings suggest that YTHDF2 in TAMs might be a promising therapeutic target for cancer immunotherapy.

2022-08-01 | GSE188400 | GEO

ACE2 Enhances Sensitivity to PD-L1 Blockade by Inhibiting Macrophage-Induced Immunosuppression and Angiogenesis [RNA-seq, anti-PD-L1 therapy]

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

ACE2 Enhances Sensitivity to PD-L1 Blockade by Inhibiting Macrophage-Induced Immunosuppression and Angiogenesis

2024-10-14 | GSE279110 | GEO

ACE2 Enhances Sensitivity to PD-L1 Blockade by Inhibiting Macrophage-Induced Immunosuppression and Angiogenesis [RNA-seq]

2024-10-14 | GSE279109 | GEO

Targeting IRE1α reprograms the tumor microenvironment and enhances anti-tumor immunity in prostate cancer [scRNA-seq2]

Project description:Unfolded protein response (UPR) is a central intracellular stress response pathway that is hijacked by tumor cells for their survival. However, how activation of UPR in cancer cells may shape the tumor microenvironment (TME) remains largely unexplored. Here, we investigated the potential role of IRE1α signaling on modulation of TME dynamics in prostate cancer (PCa). We found that IRE1α is increased in PCa patient tumors and genetic inhibition of IRE1α in syngeneic mouse PCa models, as well as in an orthotopic model, dramatically reduced tumor growth. Multiomics analysis suggested that IRE1α ablation in cancer cells significantly potentiated interferon (IFN) response and activation of immune system related pathways in the TME. Single-cell RNA-sequencing (scRNA-seq) revealed that the abundance of immunosuppressive cells, such as tumor-associated macrophages (TAMs), were markedly reduced in the IRE1α deficient tumors. Geneset Enrichment Analysis demonstrated that IFN response was significantly enriched in TAMs, cancer cells, and dendritic cells. Notably, the small molecule IRE1α inhibitor MKC8866 (ORIN1001), currently in clinical trials, reprogrammed the TME and enhanced the response to anti-PD-1 blockade therapy in syngeneic PCa mouse models. Furthermore, a novel scRNA-seq-derived TAM gene signature is strongly associated with poor PCa survival, which is reduced by the MKC8866 + anti-PD-1 combination therapy. Our findings indicate that activation of IRE1α signaling not only promotes cancer cell growth and survival, but it also interferes with anti-tumor immunity in the TME. Thus, IRE1α targeting could present a novel approach for improving anti-PD-1 immunotherapy in PCa.

2024-08-29 | GSE273458 | GEO

Targeting IRE1α reprograms the tumor microenvironment and enhances anti-tumor immunity in prostate cancer [RNA-Seq]

2024-08-29 | GSE240371 | GEO

Lenvatinib recruits cytotoxic GZMK+CD8 T cells in hepatocellular carcinoma

Project description:Lenvatinib targets multiple oncogenic kinases including vascular endothelial growth factor receptors (VEGFRs) and showed longer median progression-free survival than sorafenib, the only approved treatment for >10 years. With the successful combination therapy of anti-PD-L1 pembrolizumab and anti-VEGF bevacizumab for advanced HCC as well as encouraging experimental findings, lenvatinib was also expected to enhance anti-tumor effects by combining anti-PD-1 pembrolizumab compared to lenvatinib alone; however, the phase III clinical trial failed to show their synergetic survival benefits, highlighting the need for elucidating its mode of action in human HCC specimens after lenvatinib treatment. We performed multi-layer transcriptome analyses of surgically resected human HCC samples after lenvatinib treatment as a neo-adjuvant therapy using RNA-sequencing. Molecular pathway analyses and immunohistochemistry revealed that VEGF-mediated aberrant vascularity and cytotoxic GZMK+CD8 T cells infiltration were significantly improved in lenvatinib-treated HCC; however, the majority of these cytotoxic T cells were trapped in the intratumor fibrotic stroma, suggesting that lenvatinib-treated HCC is in the so-called excluded condition. Excluded tumors are generally believed to be less responsive to immune checkpoint inhibitors, which might be the reason the combination therapy failed to show the additive benefits.

2023-08-08 | GSE223201 | 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