Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Macrophages Coated Tumor Cluster (MCTC) Aggravated Hepatoma Invasion and Immunotherapy Resistance via Entrapping Cytotoxic T Cells to Generate Local Immune Deprivation in a M2BP-dependent manner

ABSTRACT: Immune checkpoint inhibitors (ICIs) represent promising treatment for hepatocellular carcinoma (HCC) due to abundant lymphocyte infiltration. However, some HCC patients respond poorly to ICI therapy due to the presence of various immunosuppressive factors in tumor microenvironment. Our research revealed that macrophage-coated tumor clusters (MCTCs) signified a unique spatial structural organization in HCC, correlating with diminished recurrence-free survival (RFS) and overall survival (OS) in a total of 572 HCC cases from 3 internal cohorts and 2 external validation cohort independently. Mechanistically, Tumor-derived M2BP induced MCTCs formation, and entrapped immunocompetent cells at the edge of MCTCs to induce intratumoral cytotoxic T cells exclusion and local immune deprivation. Combined treatment of anti-PD-1 antibody and Mac-2 antagonist GB1107 before MCTC formation could significantly attenuated HCC growth and inhibited HCC metastasis in vivo by recovering intratumoral infiltration of cytotoxic T cells, offering a potential strategy to enhance ICI efficacy in HCC.

ORGANISM(S): Homo sapiens

PROVIDER: GSE248907 | GEO | 2024/06/12

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

Combining Intratumoral Flu Vaccine and Systemic Pembrolizumab in Patients With Early pMMR Colorectal Cancer

Project description:Immune checkpoint inhibitor (ICI) treatment has produced striking results in patients with colorectal cancer (CRC) of the subtype deficient mismatch repair (dMMR). The majority of patients, however, have proficient MMR (pMMR) tumors, with limited effect of ICIs. The key difference between dMMR and pMMR tumors is the infiltration of cytotoxic T-cells. dMMR tumors have increased infiltration and thus increased efficacy from ICI treatment. The investigators conducted a proof of concept study where the investigators applied an intratumoral (IT) unaltered flu vaccine in ten patients with non-metastatic pMMR CRC. The intervention increased infiltration of cytotoxic T-cells and the immune checkpoint PD-L1, suggesting that IT flu vaccine primes pMMR tumors to ICI treatment. The investigators aim to test the combination of IT flu vaccine and ICI treatment in patients with non-metastatic pMMR CRC in a new trial. The hypothesis is that IT flu vaccine and ICI treatment will synergistically to induce cancer cell death.

| 63828 | ecrin-mdr-crc

Repurposing Live Attenuated Trivalent MMR Vaccine as Cost-effective Cancer ImmunotherapyRepurposing Live Attenuated Trivalent MMR Vaccine as Cost-effective Cancer Immunotherapy

Project description:In this study, we show that intratumoral injections of the trivalent measles, mumps, and rubella (MMR) live attenuated viral vaccine (LAVs) modulate a potent cytotoxic T cells immune response, resulting in tumor growth inhibition and improved survival in syngeneic mouse models of hepatocellular carcinoma (HCC) and colorectal cancer (CRC).

2022-10-27 | PXD031295 | Pride

Comprehensive Characterization of the Tumor Immune Micromilieu and its Interference with Outcome After Concurrent Chemoradiation in Patients with Locally Advanced Oropharyngeal Carcinomas

Project description:Intratumoral CD8+ T-cell infiltration in squamous cell carcinoma of the head and neck (HNSCC) has previously been linked to the efficacy of chemoradiation (CRTX) and immune checkpoint inhibitor (ICI) monotherapy. Further detailed characterization of the tumor immune-micromilieu and its influence on outcome may suggest rational CRTX-ICI combinations. In this study, the complex interaction of the tumor immune microenvironment with the efficacy of CRTX in HNSCC was analyzed. Comprehensive immune transcriptome analysis of FFPE tumor samples from patients with oropharyngeal carcinoma was used for establishing differences in tumor immune profiles according to the overall survival status. Furthermore, a composite immune signature risk score for survival prediction was developed.

2019-05-02 | GSE113282 | GEO

Interleukin-27 signaling serves as an immunological checkpoint for innate cytotoxic cells to promote hepatocellular carcinoma

Project description:While some of the inflammatory mechanisms driving hepatocellular carcinoma (HCC) had been proposed, the regulators of anti-cancer immunity in HCC remain poorly understood. We found that IL-27 receptor (IL-27R) signaling promotes HCC development in vivo. High IL-27EBI3 or IL-27RA expression correlated with poor prognosis for patients with HCC. Loss of IL-27R suppressed HCC in vivo in two different models of hepatocarcinogenesis. Mechanistically, IL-27R signaling within the tumor microenvironment restrains the cytotoxicity of innate cytotoxic lymphocytes. IL-27R ablation enhanced the accumulation and activation, while depletion or functional impairment of innate cytotoxic cells abrogated the effect of IL-27R disruption. Pharmacological neutralization of IL-27 signaling increased infiltration of innate cytotoxic lymphocytes with upregulated cytotoxic molecules and reduced HCC development. Our data reveal an unexpected role of IL-27R signaling as an immunological checkpoint regulating innate cytotoxic lymphocytes and promoting HCC of different etiologies, thus indicating a therapeutic potential for IL-27 pathway blockade in HCC

2022-05-27 | GSE200040 | GEO

Impact of Diet and aPD1 on CD8 metabolism

Project description:Only a small fraction of patients with HCC benefit from immune checkpoint inhibitor (ICI) therapy. Recently published studies suggest that HCC in patients with NASH does not respond the ICI therapy. Indeed, we demonstrate that anti-PD1 therapy is not working in several murine NASH models. CD8+ T cells were identified as the effector of anti-PD1 therapy. We observed a proinflammatory phenotype if hepatic CD8+ T cells that does not explain the inefficacy of anti-PD1 therapy in NASH. However, our study revealed an impairment of intratumoral CD8+ T cells movement abilities in NASH. Additionally, a broad reduction of metabolic fitness was observed in hepatic CD8+ T cells NASH. This was restored by metformin treatment. The combination treatment of anti-PD1 and metformin reduced intrahepatic tumor burden in NASH, a finding with important implications for NASH patients. This GEO submission contains raw files for the CD8 nsolver microarray analyses.

2022-03-31 | GSE184231 | GEO

Mouse Myeloid panel on G-MDSCs from treated tumors

Project description:Immune checkpoint inhibition (ICI) has revolutionized treatment in cancers that are naturally immunogenic by enabling infiltration of T cells into the tumor microenvironment (TME) and promoting cytotoxic signaling pathways. Tumors possessing complex immunosuppressive TME’s such as breast and pancreatic cancers present unique therapeutic obstacles as response rates to ICI remain low. Such tumors often recruit myeloid-derived suppressor cells (MDSCs) whose functioning prohibits both T-cell activation and infiltration. We attempted to sensitize these tumors to ICI using epigenetic modulation to target MDSC trafficking and function to foster a less immunosuppressive TME. We showed that combining a histone deacetylase inhibitor, entinostat (ENT), with anti–PD-1, anti–CTLA-4, [A1] [A2] or both, significantly improved tumor-free survival in both the HER2/neu transgenic breast cancer and the Panc02 metastatic pancreatic cancer mouse models. Using flow cytometry, gene expression profiling, and ex vivo functional assays, we characterized populations of tumor-infiltrating lymphocytes (TILs) and MDSCs, as well as their functional capabilities. We showed that addition of ENT to checkpoint inhibition led to significantly decreased suppression by granulocytic-MDSCs in the TME of both tumor types. We also demonstrated an increase in activated granzyme-B–producing CD8+ T effector cells in mice treated with combination therapy. Gene expression profiling of both MDSCs and TILs identified significant changes in immune-related pathways. In summary, addition of ENT to ICI significantly altered infiltration and function of innate immune cells, allowing for a more robust adaptive immune response. These findings provide a rationale for combination therapy in patients with immune-resistant tumors, including breast and pancreatic cancers.

2018-10-10 | GSE121030 | GEO

Human single cell RNA-sequencing reveals a targetable CD8+ exhausted T cell population that maintains murine low-grade glioma growth

Project description:Immune cell infiltration is a common feature of solid cancers, where T cells typically function as cytotoxic effectors to limit tumor growth, prompting therapies that activate this antineoplastic property (immune checkpoint inhibition; ICI). Unfortunately, ICI treatments have been largely ineffective for high-grade brain tumors (gliomas; HGGs). Leveraging several single-cell RNA sequencing datasets, we report greater CD8+ exhausted T cells in human pediatric low-grade gliomas (LGGs) relative to adult and pediatric HGGs. Using several preclinical mouse LGG models (Nf1-OPG mice), we showed that these PD1+/TIGIT+ CD8+ terminally exhausted T cells are restricted to the tumor tissue, where they express paracrine factors necessary for OPG growth. Importantly, ICI treatments with anti-PD1 and anti-TIGIT antibodies attenuate Nf1-OPG tumor proliferation through suppression of cytokine-mediated immune axis support, rather than by T cell-mediated cytotoxicity. Collectively, these findings establish a previously unrecognized function for CD8+ exhausted T cells as specialized regulators of LGG maintenance.

2024-10-23 | GSE244433 | GEO

Checkpoint Inhibitors Modulate Plasticity of Innate Lymphoid Cells in Peripheral Blood of Patients with Hepatocellular Carcinoma

Project description:Introduction: The role of innate lymphoid cells (ILC) in cancer and specifically in the context of hepatocellular carcinoma (HCC) is not well understood. Immune checkpoint inhibitors (ICI) have been approved for treatment of patients with HCC. The effect of ICI on ILCs has not been explored. Methods: We studied ILCs in PBMCs of 51 patients with HCC at baseline and after treatment with ICI. Flow cytometry was used to study ILC composition. Single-cell RNA-sequencing using a targeted panel of 405 immune-related genes was used to characterize the transcriptomic profiles as well as cellular trajectory of ILCs before and after ICI therapy. Intracellular cytokine staining was used to validate ILC function. Data from large patient cohorts were used to predict association with survival. Results: Characterization of the ILC subgroups in PBMCs of HCC patients revealed a significant increase in ILC1 and a decrease in ILC3 frequencies. Single cell RNA-sequencing identified a subgroup of NK-like ILCs which expressed cytotoxicity markers as well as NKp80/KLRF1. This KLRF1high-NK-like population showed low abundance in patients with HCC and was enhanced after combined anti-CTLA-4 and anti-PD-1 immunotherapy. Trajectory analysis placed this population in between ILC1 and ILC3s. The transcriptomic signature of KLRF1high NK-like ILCs was associated with better progression-free survival in HCC cohorts. Conclusions: We present a previously unknown effect of HCC tumors and ICIs on the composition and plasticity of ILCs in PBMCs. We identified a cytotoxic KLRF1high-NK-like subgroup which was associated with better survival, absent in untreated HCC patients, and enhanced upon ICI immunotherapy. Thus, ILCs from PBMC can be used to study changes in the innate immune system under immunotherapy.

2022-06-23 | GSE195648 | GEO

A Single-Cell Atlas of the Multicellular Ecosystem of Primary and Metastatic Hepatocellular Carcinoma

Project description:Hepatocellular carcinoma (HCC) represents a paradigm of the relation between tumor microenvironment and tumor development. Here, we generated > 70,000 single-cell transcriptomes for 10 HCC patients from four relevant sites: primary tumor, portal vein tumor thrombus (PVTT), metastatic lymph node and non-tumor liver. We discovered a cluster of antitumor central memory T cells enriched in intratumoral tertiary lymphoid structures (TLSs) of HCC. We found chronic HBV/HCV infection increases the infiltration of CD8+ T cells in tumors but aggravates the exhaustion of tumor-infiltrating lymphocytes. We identified MMP9+ macrophages to be terminally differentiated tumor-associated macrophages (TAMs) and two distinct differentiation trajectories are related to their accumulation. We further demonstrated MMP9+ TAMs can promote HCC cells migration, invasion and angiogenesis. Our data also revealed the heterogeneous population of malignant hepatocytes and found they might play multifaceted roles in shaping the immune microenvironment of HCC. Finally, we identified seven TME subtypes of HCC that can predict patient prognosis. Collectively, this large-scale, single-cell atlas deepens our understanding of the ecosystem in primary and metastatic HCCs, might facilitating identification of new immune therapy strategies for this malignancy.

2020-04-30 | GSE149614 | GEO

TMT proteomics analysis of B16/F10

Project description:The recently described role of RNA methylation in regulating immune cell infiltration into tumors has attracted interest, given its potential impact on immunotherapy response. YTHDF1 is a versatile and powerful m6A reader, but the understanding of its impact on immune evasion is limited. Here, we revealed that tumor-intrinsic Ythdf1 drives immune evasion and immune checkpoint inhibitor (ICI) resistance. TMT proteomics analysis was performed to identify the altered protein.

2022-12-06 | PXD036938 | Pride

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