Dataset Information

Activated neutrophils exert myeloid-derived suppressor cell activity, damaging T cells beyond repair

ABSTRACT: Myeloid-derived suppressor cells (MDSCs) have the capacity to suppress T cell-mediated immune responses, and impact clinical outcome of cancer, infections and transplantation settings. Although MDSCs were initially described as bone-marrow-derived immature myeloid cells (either monocytic [m-MDSC] or granulocytic [g-MDSC]), also mature neutrophils have been shown to exert MDSC activity towards T cells, in ways that so far remained unclear. In this study, we demonstrate that human neutrophils – both from healthy donors and cancer patients – do not exert MDSC activity unless they are activated. Using neutrophils with genetically well-defined defects, we found that reactive oxygen species (ROS) and granule-derived constituents are required for MDSC activity after direct CD11b-dependent neutrophil-T cell interactions. Besides these cellular interactions, neutrophils were engaged in the uptake of pieces of T cell membrane, a process called trogocytosis. Together, these interactions led to changes in T cell morphology, mitochondrial dysfunction and ATP depletion, as indicated by electron microscopy, mass spectrometry and metabolic parameters. Our studies characterize the different steps by which activated mature neutrophils induce functional T cell non-responsiveness and irreparable cell damage.

INSTRUMENT(S): Orbitrap Fusion ETD

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Primary Cell, T Cell

SUBMITTER: Cathelijn Aarts

LAB HEAD: T.W. Kuijpers

PROVIDER: PXD010508 | Pride | 2020-05-07

REPOSITORIES: Pride

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Activated neutrophils exert myeloid-derived suppressor cell activity damaging T cells beyond repair.

Aarts Cathelijn E M CEM Hiemstra Ida H IH Béguin Eelke P EP Hoogendijk Arjan J AJ Bouchmal Souhailla S van Houdt Michel M Tool Anton T J ATJ Mul Erik E Jansen Machiel H MH Janssen Hans H van Alphen Floris P J FPJ de Boer Jan-Paul JP Zuur Charlotte L CL Meijer Alexander B AB van den Berg Timo K TK Kuijpers Taco W TW

Blood advances 20191101 22

Myeloid-derived suppressor cells (MDSCs) have the capacity to suppress T-cell-mediated immune responses and impact the clinical outcome of cancer, infections, and transplantation settings. Although MDSCs were initially described as bone marrow-derived immature myeloid cells (either monocytic or granulocytic MDSCs), mature neutrophils have been shown to exert MDSC activity toward T cells in ways that remain unclear. In this study, we demonstrated that human neutrophils from both healthy donors an ...[more]

PMID: 31738831

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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.

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