Dataset Information

Integrated Multi-Omics Profiling for the Identification of Markers Associated with Myeloid-Derived Suppressor Cells in Human Isogenic Cell Line Models of Neutrophils and Myeloid-Derived Suppressor Cells

ABSTRACT: This study presents an integrative analysis identifying a 26-gene signature associated with myeloid-derived suppressor cells (MDSCs) in cancer, leveraging mass spectrometry proteomics data, RNA sequencing data and external datasets from lung and head and neck cancers. The genes within this signature were found to correlate positively with MDSC infiltration and negatively with neutrophil and CD8+ T cell presence in the tumor microenvironment. Clinically, this signature showed a significant association with reduced survival rates in metastatic melanoma patients treated with PD1 inhibitors, highlighting its potential as a prognostic biomarker in cancer therapy. This study enhances our understanding of MDSCs in oncology and opens new avenues for targeted therapeutic strategies against MDSC-mediated immunosuppression in the tumor microenvironment.

INSTRUMENT(S): Orbitrap Fusion Lumos

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Cell Culture

SUBMITTER: JIN HU

LAB HEAD: MS facility

PROVIDER: PXD048934 | Pride | 2024-06-22

REPOSITORIES: Pride

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Publications

Protein Signature Differentiating Neutrophils and Myeloid-Derived Suppressor Cells Determined Using a Human Isogenic Cell Line Model and Protein Profiling.

Zhang Yuting Y Hu Jin J Zhang Xiashiyao X Liang Minzhi M Wang Xuechun X Gan Dailin D Li Jun J Lu Xuemin X Wan Jun J Feng Shan S Lu Xin X

Cells 20240507 10

Myeloid-derived suppressor cells (MDSCs) play an essential role in suppressing the antitumor activity of T lymphocytes in solid tumors, thus representing an attractive therapeutic target to enhance the efficacy of immunotherapy. However, the differences in protein expression between MDSCs and their physiological counterparts, particularly polymorphonuclear neutrophils (PMNs), remain inadequately characterized, making the specific identification and targeting of MDSCs difficult. PMNs and PMN-MDSC ...[more]

PMID: 38786019

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Project description:Myeloid-derived suppressor cells (MDSCs) are immature myeloid cells that accumulate in the tumor microenvironment of most cancer patients. There MDSCs suppress both adaptive and innate immune responses, hindering immunotherapies. Moreover, many cancers are accompanied by inflammation, a processes that further intensifies MDSC suppressive activity, causing aggressive tumor progression and metastasis. MDSCs collected from tumor-bearing mice profusely release nano-scale membrane-bound extracellular vesicles, called exosomes, which carry biologically active proteins between cells and contribute directly to the immune suppressive functions of MDSC. Many studies on other cell types have shown that exosomes may also carry microRNAs (miRNAs) and messenger RNAs (mRNAs) which can also be transferred to surrounding and distant cells. However, to the best of our knowledge, the miRNA and mRNA cargo of MDSC-derived exosomes has not yet been interrogated. This study aims to identify and quantify the cargo of MDSC and their immunosuppressive exosomes to gather knowledge that can offer insights on the mechanisms by which MDSCs contribute to immune suppression, focusing on the role of exosomes as intercellular communication mediators in the tumor microenvironment. In order to achieve our objective a well-established mouse model based on a conventional mammary carcinoma (4T1 cells) and heightened inflammation (4T1 transduced to express the cytokine interleukin-1b) was used. We provide evidence that MDSC-derived exosomes carry proteins, mRNAs and miRNAs. Relative quantitation demonstrated quantitative differences between the exosome cargo and the cargo of their parental cells, supporting the hypothesis that selective loading into the exosomes is possible. Additionally, quantitative and functional analyses of the exosome cargo generated under conventional and heightened inflammation conditions are consistent with clinical observations that inflammation is linked to cancer development.

Project description:Myeloid-derived suppressor cells (MDSCs) are key players in immune evasion, tumor progression and metastasis. MDSCs accumulate under various pathological states, and fall into two functionally and phenotypically distinct subsets: polymorphonuclear (PMN)-MDSCs and monocytic (M)-MDSCs. These subsets have been studied extensively in humans and mice, yet to date no study has identified MDSC subsets in dogs with spontaneous tumors. As dogs are an excellent model for human tumor development and progression, we set out to identify PMN-MDSCs and M-MDSCs in clinical canine oncology patients. We identified MDSCs as hypodense MHC class II-CD5-CD21-CD11b+ cells and show for the first time that they can also be subdivided into polymorphonuclear (CADO48A+CD14-) and monocytic (CADO48A-CD14+) subsets. The transcriptomic signatures of PMN-MDSCs and M-MDSCs are distinct from each other and from those of conventional polymorphonuclear (PMN) and monocytic cells, respectively. Notably, bioinformatic analyses reveal a statistically significant similarity between canine and previously published human MDSC gene expression patterns. As in humans, peripheral blood frequencies of canine PMN-MDSCs and M-MDSCs are significantly different in dogs with cancer compared to healthy control dogs (PMN-MDSCs: p < .001; M-MDSCs: p < .01). Furthermore, a comparison of our canine MDSC RNA-seq data with transcriptomic results previously published for human and murine MDSCs highlights five commonly upregulated genes in PMN-MDSCs in all species, suggesting that these genes are evolutionarily conserved and functionally important. Interestingly, one gene has previously been implicated in PMN-MDSC function (MMP8), but four genes (LTF, LCN2, CAMP, EBP41L3) are novel in the context of PMN-MDSCs. Our findings therefore demonstrate for the first time that dogs have two distinct populations of MDSCs, characterized by specific phenotypic and transcriptomic signatures that share key features of human MDSC subsets. Importantly, by leveraging the power of evolution, we have identified additional conserved genes in PMN-MDSCs of multiple species which may play a role in MDSC function. Our findings therefore validate the dog as a model for studying MDSCs in the context of cancer.

Dataset Information

Integrated Multi-Omics Profiling for the Identification of Markers Associated with Myeloid-Derived Suppressor Cells in Human Isogenic Cell Line Models of Neutrophils and Myeloid-Derived Suppressor Cells

Publications

Protein Signature Differentiating Neutrophils and Myeloid-Derived Suppressor Cells Determined Using a Human Isogenic Cell Line Model and Protein Profiling.

Similar Datasets

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