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Targeting an immunoregulatory dendritic cell-CCL22 program alleviates radioresistance

ABSTRACT: Targeting an immunoregulatory dendritic cell-CCL22 program alleviates radioresistance

PROVIDER: PRJNA1094396 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR28506871_1.fastq.gz	Fastqsanger.gz
	SRR28506871_2.fastq.gz	Fastqsanger.gz
	SRR28506872_1.fastq.gz	Fastqsanger.gz
	SRR28506872_2.fastq.gz	Fastqsanger.gz
	SRR28506873_1.fastq.gz	Fastqsanger.gz

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Targeting an immunoregulatory dendritic cell-CCL22 program alleviates radioresistance

Project description:Purpose: Radiation-mediated immune suppression limits efficacy and is a barrier in cancer therapy. Radiation induces negative regulators of tumor immunity including regulatory T cells (Treg). Mechanisms underlying Treg infiltration after radiotherapy (RT) are poorly defined. Given that dendritic cells (cDC) maintain Treg we sought to identify and target cDC signaling to block Treg infiltration after radiation. Experimental Design: Transcriptomics and high dimensional flow cytometry revealed changes in murine tumor cDC that not only mediate Treg infiltration after RT, but associate with worse survival in human cancer datasets. Antibodies perturbing a cDC-CCL22-Treg axis were tested in syngeneic murine tumors. A prototype interferon-anti-epidermal growth factor receptor fusion protein (αEGFR-IFNα) was examined to block Treg infiltration and promote a CD8+ T cell response after RT. Results: Radiation expands a population of mature cDC1 enriched in immunoregulatory markers that mediates Treg infiltration via the Treg-recruiting chemokine CCL22. Blocking CCL22 or Treg depletion both enhanced RT efficacy. αEGFR-IFNα blocked cDC1 CCL22 production while simultaneously inducing an antitumor CD8+ T cell response to enhance RT efficacy in multiple EGFR-expressing murine tumor models, including following systemic administration. Conclusions: We identify a previously unappreciated cDC mechanism mediating Treg tumor infiltration after RT. Our findings suggest blocking the cDC1-CCL22-Treg axis augments RT efficacy. αEGFR-IFNα added to RT provided robust antitumor responses better than systemic free interferon administration, and may overcome clinical limitations to interferon therapy. Our findings highlight the complex behavior of cDC after RT and provide novel therapeutic strategies for overcoming RT-driven immunosuppression to improve RT efficacy.

2024-04-17 | GSE262864 | GEO

An activation-induced immunoregulatory and tissue-residency program modulated by c-MAF in human memory Th17 cells [ChIP-seq] [RNA-seq]

Project description:T cell effector function is largely mediated through the release of pro-inflammatory cytokines that need to be tightly regulated to avoid tissue damage. Here we show that the anti-inflammatory cytokine IL-10 is produced by a subset of recently-activated human Th17 cells and is controlled by the selective up-regulation of the transcription factor c-MAF. In addition, recently-activated IL-10+ Th17 cells upregulate immunoregulatory genes and genes characteristic of tissue resident T cells. In contrast, recently activated IL-10- Th17 cells maintain a pro-inflammatory gene expression profile and upregulate homing receptors to recirculate from tissues to blood. By integrating ChIP-seq and RNA-seq analyses, we demonstrate that c-MAF plays a key role in orchestrating the immune-regulatory and tissue residency program of IL-10+ Th17 cells by binding to a large number of non-promoter regions with enhancer-like features. Thus, c-MAF may represent a relevant factor discriminating between immunoregulatory and pro-inflammatory human Th17 cells.

2018-09-12 | GSE101389 | GEO

USP9X-mediated KDM4C deubiquitination promotes lung cancer radioresistance by epigenetically inducing TGFβ2 transcription

Project description:Radioresistance is regarded as the main barrier to effective radiotherapy in lung cancer. However, the underlying mechanisms of radioresistance remain elusive. Here, we show that lysine-specific demethylase 4C (KDM4C) is overexpressed and correlated with poor prognosis in lung cancer patients. We provide evidence that genetical or pharmacological inhibition of KDM4C impairs tumorigenesis and radioresistance in lung cancer in vitro and in vivo. Moreover, we uncover that KDM4C upregulates TGFβ2 expression by directly reducing H3K9me3 level at the TGFβ2 promoter and then activates TGF-β/Smad/ATM signaling to confer radioresistance in lung cancer. Using tandem affinity purification technology, we further identify deubiquitinase USP9X as a critical binding partner which deubiquitinates and stabilizes KDM4C. More importantly, depletion of USP9X impairs TGF-β/Smad signaling and radioresistance by destabilizing KDM4C in lung cancer cells. Thus, our findings demonstrate that USP9X-mediated KDM4C deubiquitination activates TGF-β/Smad signaling to promote radioresistance, suggesting that targeting KDM4C may be a promising radiosensitization strategy in the treatment of lung cancer.

2021-07-14 | GSE136404 | GEO

Megakaryocyte derived immunoregulatory cells regulate host-defense immunity against bacterial pathogens

Project description:Here, using single-cell sequencing we identified an MK derived immunoregulatory cell population, which plays an important role in host-protective responses against bacteria. In contrast to platelet-generating MKs, MK derived immunoregulatory cells highly express immune response genes and chemokines.

2022-03-24 | GSE168224 | GEO

Proteomic signatures of radioresistance: Alteration of inflammation, angiogenesis and metabolism-related factors in radioresistant oesophageal adenocarcinomav

Project description:The clinical management of locally advanced oesophageal adenocarcinoma (OAC) commonly involves neoadjuvant chemoradiotherapy (CRT), but complete pathological response to CRT only occurs in 20-30% of patients, as radioresistance remains a major clinical challenge. In this study we used an established isogenic cell line model of radioresistant OAC to detect proteomic signatures of radioresistance in order to identify novel potential molecular and cellular targets of radioresistance in OAC. Intracellular proteins obtained from radiosensitive (OE33P) and radioresistant (OE33R) cells were subjected to LC-MS/MS analysis. We identified 5785 proteins of which 251 were significantly modulated in OE33R cells, when compared to OE33P. Gene ontology and pathway analysis of the significantly modulated proteins demonstrated altered metabolism in radioresistant cells accompanied by an inhibition of apoptosis in OE33R cells. In addition, radioresistant cells were predicted to have an activation of inflammatory and angiogenic pathways when compared to the radiosensitive cells. For the first time, we performed a comprehensive proteomic profiling of our established isogenic cell line model of radioresistant OAC, providing insights into the molecular and cellular pathways which regulates radioresistance in OAC, and we provided pathway specific signatures of radioresistance that will aid further studies on the development of targeted therapies and personalised approaches to radiotherapy, with the ultimate goal of improving response to radiotherapy in cancer patients.

2022-08-18 | PXD020303 | Pride

Expression analysis of miRNA involved in radioresistance of oral squamous cell carcinoma.

Project description:Oral squamous cell carcinoma (OSCC) is not significant improved in prognosis despite advancement in treatments. The presence of treatment resistant OSCC is responsible for stagnation in the survival rate. The inter-cellular communications between tumor cells is one of the molecular mechanisms involved in the acquisition of treatment resistance of OSCC. Extracellular vesicles (EVs) and encapsulated miRNAs are important mediators of the inter-cellular communication. We searched for miRNAs involved in radioresistance of OSCC, in order to elucidate the mechanism of acquisition of radioresistance

2021-04-02 | GSE160122 | GEO

Tumor cell-intrinsic Piezo2 drives radioresistance by impairing CD8+ T cell stemness maintenance

Project description:Piezo2 impedes stemness maintenance of CD8+ T cells by downregulating IL-15 production after radiotherapy, thereby leading to cancer radioresistance.

2024-08-08 | GSE236345 | GEO

Tumor cell-intrinsic Piezo2 drives radioresistance by impairing CD8+ T cell stemness maintenance

Project description:Piezo2 impedes stemness maintenance of CD8+ T cells by downregulating IL-15 production after radiotherapy, thereby leading to cancer radioresistance.

2024-08-08 | GSE236339 | GEO

miRNAs were involved in the radioresistance of esophageal squamous cell carcinoma

Project description:Cancer cells associated with radioresistance are likely to give rise to local recurrence and distant metastatic relapse. However, it remains unclear whether specific miRNAs have direct roles in radioresistance and/or prognosis. In this study, we performed a human miRNA expression array analysis to identify miRNAs upregulated or downregulated in the radioresistant cells. To confirm the results, we selected several candidate miRNAs according to the fold change and function of miRNAs, and detected their expression levels in the radioresistant cells and their parental cells using qRT-PCR. Moreover, we further investigate that specific miRNAs predicts pathological response to preoperative radiotherapy in locally advanced ESCC

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