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Ferroptosis of tumor-associated neutrophils is immunosuppressive and promotes tumor growth

ABSTRACT: Ferroptosis is a non-apoptotic form of regulated cell death triggered by the discoordination of regulatory redox mechanisms culminating in massive peroxidation of polyunsaturated phospholipids. The development of the concept of ferroptosis stemmed from an active search for alternatives to apoptosis in cancer cells. Ferroptosis inducers have shown remarkable effectiveness in killing tumor cells in vitro, yet with no obvious success in experimental animal models, with a notable exception of immune-deficient mice 1,2. This suggests the potential poorly understood contribution of ferroptosis on immune cells. Pathologically activated neutrophils (PMN), termed myeloid-derived suppressor cells (PMN-MDSC), are major negative regulators of anti-tumor immunity3-5. Here, we found that PMN-MDSC in the tumor microenvironment (TME), spontaneously die by ferroptosis. While decreasing the presence of PMN-MDSC, ferroptosis induces the release of oxygenated lipids and limits mouse and human T cell activity. In immune-competent mice, genetic and pharmacological inhibition of ferroptosis abrogates suppressive activity of PMN-MDSC, reduces tumor progression, and synergizes with immune checkpoint blockade (ICB) to suppress the tumor growth. In contrast, induction of ferroptosis in immune-competent mice promotes tumor growth. Thus, ferroptosis is a unique and targetable immunosuppressive mechanism of PMN-MDSC in the TME that can be pharmacologically modulated to limit tumor progression.

ORGANISM(S): Mus musculus

PROVIDER: GSE205371 | GEO | 2022/09/19

REPOSITORIES: GEO

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Ferroptosis of tumor-associated neutrophils is immunosuppressive and promotes tumor growth

Project description:Ferroptosis is a non-apoptotic form of regulated cell death triggered by the discoordination of regulatory redox mechanisms culminating in massive peroxidation of polyunsaturated phospholipids. The development of the concept of ferroptosis stemmed from an active search for alternatives to apoptosis in cancer cells. Ferroptosis inducers have shown remarkable effectiveness in killing tumor cells in vitro, yet with no obvious success in experimental animal models, with a notable exception of immune-deficient mice 1,2. This suggests the potential poorly understood contribution of ferroptosis on immune cells. Pathologically activated neutrophils (PMN), termed myeloid-derived suppressor cells (PMN-MDSC), are major negative regulators of anti-tumor immunity3-5. Here, we found that PMN-MDSC in the tumor microenvironment (TME), spontaneously die by ferroptosis. While decreasing the presence of PMN-MDSC, ferroptosis induces the release of oxygenated lipids and limits mouse and human T cell activity. In immune-competent mice, genetic and pharmacological inhibition of ferroptosis abrogates suppressive activity of PMN-MDSC, reduces tumor progression, and synergizes with immune checkpoint blockade (ICB) to suppress the tumor growth. In contrast, induction of ferroptosis in immune-competent mice promotes tumor growth. Thus, ferroptosis is a unique and targetable immunosuppressive mechanism of PMN-MDSC in the TME that can be pharmacologically modulated to limit tumor progression.

2022-09-24 | GSE213861 | GEO

Transcriptome comparsion of WT and CD300ld KO PMN-MDSC

Project description:Polymorphonuclear myeloid-derived suppressor cell (PMN-MDSC), also named pathologically activated neutrophil, is a critical component of tumor microenvironment (TME), playing crucial roles in tumor progression and therapy resistance. CD300ld is specifically expressed in normal neutrophils and is upregulated in PMN-MDSCs upon tumor bearing. CD300ld knockout (KO) inhibits the development of multiple tumor types in a PMN-MDSC-dependent manner. Here, we compared the transcriptome of PMN-MDSCs from WT mice and CD300ld KO mice.

2023-06-26 | GSE199602 | GEO

Effect of systemic depletion of glutamine via PEGylated glutaminase on CT26 tumor tissue.

Project description:Proliferating cancer cells are addicted to glutamine for biomass synthesis and energy generation. We here enzymatically deplete circulating glutamine in mice and report how cancer cells adapt to low circulating glutamine and document immunological changes in the tumor microenvironment (TME) upon glutamine depletion in CT26 tumor model. We show that cancer cells adapt to low glutamine by diverting intracellular glutamine flux to nucleotide synthesis and downregulating global translation. Through immune cell deconvolution and GSEA, we show that systemic glutamine depletion is immunsosuppressive and marked by accumulaton of PMN-MDSC in the TME.

2024-04-16 | GSE247472 | GEO

Transcriptome comparison of PMN-MDSCs and and normal neutrophils

2023-06-26 | GSE199601 | GEO

Unique features of co-existence of classical neutrophils and polymorphonuclear myeloid-derived suppressor cells in cancer

Project description:In this study, using single cell RNAseq, cell mass-spectrometry, flow cytometry, and functional analysis, we characterized the heterogeneity of polymorphonuclear neutrophils (PMN) in cancer. We described three populations of PMN in tumor-bearing mice: classical PMN, polymorphonuclear myeloid derived suppressor cells (PMN-MDSC), and activated PMN-MDSC with potent immune suppressive activity. In spleens of mice, PMN-MDSC gradually replaced PMN during tumor progression. Activated PMN-MDSC were found only in tumors where they were present at the very early stages of the disease. These populations of PMN in mice could be separated based on the expression of CD14. In peripheral blood of cancer patients, we identified two distinct populations of PMN with characteristics of classical PMN and PMN-MDSC. Gene signature of tumor PMN-MDSC was similar to that in mouse activated PMN-MDSC and was closely associated with negative clinical outcome in cancer patients. Thus, we provided evidence that PMN-MDSC is a distinct population of PMN with unique features and potential for selective targeting opportunities

2021-01-14 | GSE163834 | GEO

Fatty acid transporter 2 regulates lipid metabolism and suppressive function of neutrophils in cancer

Project description:Polymorphonuclear myeloid derived suppressor cells (PMN-MDSC) are pathologically activated neutrophils that accumulate in cancer and many other pathologic conditions. PMN-MDSC are critically important for the regulation of immune responses in cancer, promotion of tumor progression, and metastases. Despite the recent advances in understanding of the PMN-MDSC biology, the mechanisms responsible for pathological activation of neutrophils are not well defined, which limit selective targeting of PMN-MDSC. Here, we report that mouse and human PMN-MDSC exclusively up-regulate fatty acid transporter protein 2 (FATP2). Over-expression of FATP2 in PMN-MDSC was controlled by GM-CSF, through the activation of STAT5 transcription factor. Genetic ablation of FATP2 abrogated the suppressive activity of PMN-MDSC in spleens and tumors. FATP2 in neutrophils promoted accumulation of oxidized lipids. However, the main mechanism of FATP2 mediated suppressive activity of PMN-MDSC involved uptake of arachidonic acid and synthesis of prostaglandin E2. The selective pharmacological inhibition of FATP2 abrogated activity of PMN-MSC and substantially delayed tumor progression. In combination with check-point inhibitors it blocked tumor progression in mice. Thus, FATP2 mediates acquisition of immune suppressive activity by PMN-MDSC and represents a new target to inhibit the functions of PMN-MDSC and improve the effect of immunotherapy of cancer.

2019-05-09 | GSE126885 | GEO

Lectin-type oxidized LDL receptor 1 defines population of polymorphonuclear myeloid-derived suppressor cells in cancer patients

Project description:Polymorphonuclear myeloid-derived suppressor cells (PMN-MDSC) are important regulators of immune responses and promoters of tumor progression in cancer1,2. The heterogeneity of these cells as well as their distinction from neutrophils hampers the progress in understanding of the biology and clinical significance of these cells. PMN-MDSC had a distinct gene signature from neutrophils isolated from the same patients with most prominent changes in genes associated with endoplasmic reticulum (ER) stress response. Surprisingly, low-density lipoprotein (LDL) was one of the most enriched gene regulators and oxidized LDL receptor 1 (OLR1) was one of the most overexpressed genes in PMN-MDSC. Lectin-type oxidized LDL receptor 1 (LOX-1) encoded by OLR1 was expressed in only 0.7% of neutrophils in peripheral blood of healthy donors, whereas 5-15% of neutrophils in cancer patients and 15-50% of neutrophils in tumor tissues were LOX-1+. In contrast to their LOX-1- counterparts, LOX-1+ neutrophils had gene signature, biochemical and functional characteristics of PMN-MDSC. Induction of ER stress in neutrophils from healthy donors up-regulated LOX-1 expression and converted these cells to suppressive PMN-MDSC. Thus, PMN-MDSC have distinct gene signature and LOX-1 can define this population of cells, which may provide new insight to the biology and clinical evaluation of these cells. Examination of LOX1+/LOX1- and PMN/MDSC cells in cancer patient samples

2016-07-22 | E-GEOD-79404 | biostudies-arrayexpress

Tumor-infiltrating monocytic myeloid-derived suppressor cells mediate CCR5-dependent recruitment of regulatory T cells favoring tumor growth

Project description:Analysis of MDSC subsets from naive blood and RMA-S blood and RMA-S tumor, respectively. Tumor-infiltrating MO-MDSCs changed their expression pattern compared to blood and exhibited high levels of chemokines Total RNA obtained from PMN-MDSCs and MO-MDSCs from naive blood or from blood and tumor of RMA-S bearing mice

2012-10-17 | E-GEOD-41620 | biostudies-arrayexpress

Whole genome expression profile of human decidual PMN-MDSC in normal pregnancy and unexplained recurrent pregnancy loss

Project description:Polymorphonuclear myeloid-derived suppressor cell (PMN-MDSC) accumulate in maternal-fetal interface during pregnancy and play a role in maintenance of immune tolerance. Decreased PMN-MDSC is associated with pregnancy complications such as unexplained recurrent pregnancy loss (URPL). Whether PMN-MDSC function is different between normal pregnancy (NP) and URPL remains unexplored. Here we performed whole genome expression profile of 3 decidual PMN-MDSC from normal early pregnancy and 3 decidual PMN-MDSC from URPL. Total RNA were extracted. Cy5-labeled aRNA was hybridized and scanned on a G2505C Agilent Microarray Scanner with Agilent 0.1 XDR software. The gene expression pattern of the PMN-MDSC was significantly different between the NP group and the URPL group.

2020-06-30 | GSE139180 | GEO

Proteomic Signatures of Myeloid Derived Suppressor Cells from Liver and Lung Metastases Reveal Functional Divergence and Potential Therapeutic Targets

Project description:Myeloid Derived Suppressor Cells (MDSCs) promote immunosuppressive activities in the tumor microenvironment (TME), resulting in increased tumor burden and diminishing the anti-tumor response of immunotherapies. While primary and metastatic tumors are typically the focal points of therapeutic development, the immune cells of the TME are uniquely programmed by the tissue of the metastatic site. In particular, MDSCs are programmed uniquely within different organs in the context of tumor progression. Given that MDSC plasticity is shaped by the surrounding environment, the proteome of MDSCs from different metastatic sites are hypothesized to be unique. A bottom-up proteomics approach using Sequential Window Acquisition of All Theoretical Mass Spectra (SWATH-MS) was used to quantify the proteome of CD11b+ cells derived from murine liver metastases (LM) and lung metastases (LuM). A comparative proteomics workflow was employed to compare MDSC proteins from LuM (LuM-MDSC) and LM (LM-MDSC) while also elucidating common signaling pathways, protein function, and possible drug-protein interactions.

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