Ferroptosis of tumour neutrophils causes immune suppression in cancer

Kim, Rina; Hashimoto, Ayumi; Markosyan, Nune; Tyurin, Vladimir A.; Tyurina, Yulia Y.; Kar, Gozde; Fu, Shuyu; Sehgal, Mohit; Garcia-Gerique, Laura; Kossenkov, Andrew V.; Gebregziabher, Bereket A.; Tobias, John W.; Hicks, Kristin C.; Halpin, Rebecca; Cvetešić, Nevena; Deng, Hui; Donthireddy, Laxminarasimha; Greenberg, Andrew S.; Nam, Brian; Vonderheide, Robert H.; Nefedova, Yulia; Kagan, Valerian E.; Gabrilovich, Dmitry I.

doi:10.1038/s41586-022-05443-0

Cited by 198 publications

(196 citation statements)

References 57 publications

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“… 82 On the other hand, ferroptosis of immune cells promotes tumor development. The latest study conducted by Kim et al 83 showed that ferroptosis of pathologically activated neutrophils-termed myeloid-derived suppressor cells (PMN-MDSC) in immunologically normal hosts promoted tumor growth by limiting anti-tumor immunity and inducing ferritin hypertrophy promoted tumor growth. Ferritin deposition is a unique immunosuppressant mechanism of PMN-MDSCs in the tumor microenvironment, which can be regulated by targeted drugs to limit tumor development.…”

Section: Ferroptosis In Hepatocellular Carcinoma (Hcc)mentioning

confidence: 99%

The Emerging Role of Ferroptosis in Various Chronic Liver Diseases: Opportunity or Challenge

Zhu¹,

Luo²,

Zhu³

et al. 2023

JIR

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Ferroptosis is a recently identified iron-dependent form of intracellular lipid peroxide accumulation-mediated cell death. Different from other types of cell death mechanisms, it exhibits distinct biological and morphological features characterized by the loss of lipid peroxidase repair activity caused by glutathione peroxidase 4, the presence of redox-active iron, and the oxidation of phospholipids-containing polyunsaturated fatty acids. In recent years, studies have shown that ferroptosis plays a key role in various liver diseases such as alcoholic liver injury, non-alcoholic steatohepatitis, liver cirrhosis, and liver cancer. However, the mechanism of ferroptosis and its regulation on chronic liver disease are controversial among different types of cells in the liver. Herein, we summarize the current studies on mechanism of ferroptosis in chronic liver disease, aiming to outline the blueprint of ferroptosis as an effective option for chronic liver disease therapy.

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Section: Ferroptosis In Hepatocellular Carcinoma (Hcc)mentioning

confidence: 99%

The Emerging Role of Ferroptosis in Various Chronic Liver Diseases: Opportunity or Challenge

Zhu¹,

Luo²,

Zhu³

et al. 2023

JIR

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“…Mutant KRAS polarizes macrophages into an M2-like protumor phenotype to promote pancreatic cancer progression [ 19 ]. Additionally, the spontaneous ferroptosis of tumor neutrophils in the tumor microenvironment limits the activity of infiltrated T cells to promote tumor growth [ 20 ]. Therefore, ferroptosis seems to be a double-edged sword in tumorigenesis.…”

Section: Introductionmentioning

confidence: 99%

BACH1-induced ferroptosis drives lymphatic metastasis by repressing the biosynthesis of monounsaturated fatty acids

et al. 2023

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Esophageal squamous cell carcinoma (ESCC) is one of the fatal malignancies worldwide. It has an increased propensity to metastasize via lymphogenous routes in an early stage. The prognosis of patients with lymph node metastases (LNM) is often worse than that of patients without metastases. Although several factors have been found to influence metastasis, the mechanisms of preference for specific metastatic routes remain poorly understood. Herein, we provide evidence that the intrinsic hypersensitivity of tumor cells to ferroptosis may proactively drive lymphatic metastasis. Serum autoantibodies associated with LNM of early ESCC were screened using a whole-proteome protein array containing 19 394 human recombinant proteins, and an anti-BACH1 autoantibody was first identified. Pan-cancer analysis of ferroptosis-related genes with preferential lymphatic metastasis and preferential hematogenous metastasis based on The Cancer Genome Atlas data was performed. Only BACH1 showed significant overexpression in tumors with preferential lymphatic metastasis, whereas it was downregulated in most tumors with preferential nonlymphatic metastasis. In addition, it was found that the serum levels of autoantibodies against BACH1 were elevated in early-stage patients with LNM. Interestingly, BACH1 overexpression and ferroptosis induction promoted LNM but inhibited hematogenous metastasis in mouse models. Transcriptomic and lipidomic analyses found that BACH1 repressed SCD1-mediated biosynthesis of monounsaturated fatty acids, especially oleic acid (OA). OA significantly attenuated the ferroptotic phenotypes and reversed the metastatic properties of BACH1-overexpressing cells. OA addition significantly rescued the ferroptotic phenotypes and reversed the metastatic properties of BACH1-overexpressing cells. Importantly, the concentration gradient of OA between primary lesions and the lymph resulted in the chemoattraction of tumor cells to promote invasion, thus facilitating lymphatic metastasis. BACH1-induced ferroptosis drives lymphatic metastasis via the BACH1-SCD1-OA axis. More importantly, this study confirms that ferroptosis is a double-edged sword in tumorigenesis and tumor progression. The clinical application of ferroptosis-associated agents requires a great caution.

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“…We thus wanted to compare the transcriptional characteristics of immune suppressive neutrophils induced by colitis with those of PMN-MDSCs in tumor-bearing mice. We aggregated our single-cell RNA sequencing data with those described in [26, 27, 29] and extracted cells based on PMN cell markers Ly6g, Cxcr2, and S100a8 (Fig. S6D).…”

Section: Resultsmentioning

confidence: 99%

“…PMN-MDSCs were characterized in tumor-bearing mice and human patients and are primarily produced in spleens via EMH [26][27][28]. These cells were further characterized recently by single-cell RNA sequencing [26,27,29]. We thus wanted to compare the transcriptional characteristics of immune suppressive neutrophils induced by colitis with those of PMN-MDSCs in tumor-bearing mice.…”

Section: Neutrophils In Colitic Wnt5 Dko Spleen Are Transcriptomicall...mentioning

confidence: 99%

Loss of WNT5 Proteins Reprograms Neutrophils in the Spleen to Provide Protection for DSS-Induced Colitis

Luan

Wang

et al. 2023

Preprint

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WNT5A and WNT5B are two close homologs, both of which are implicated in the pathogenesis of inflammatory bowel diseases. However, the roles these two proteins play in the disease remain largely uncharacterized. Here, we report that double knockout of Wnt5a and Wnt5b (Wnt5 DKO) protects mice from Dextran Sodium Sulfate (DSS)-induced colitis in mice, accompanied with greater splenomegaly, stronger expansion of peripheral myeloid cells, and less colonic CD8+ T cell granzyme B expression than those of the control mice. Depletion of neutrophils or splenectomy abrogates the phenotypic differences between Wnt5 DKO and control mice largely by exacerbating colitis phenotypes and increasing colonic CD8+ T cell GZMB expression in the Wnt5 DKO mice. In addition, neutrophils from the Wnt5 DKO colitic mice exert stronger suppression of CD8+ T cells than those from the control mice in culture. Single-cell RNA sequencing and proteomic analyses indicate that neutrophils from DSS-treated Wnt5 DKO mice are of hyper-immunosuppressive and hypo-inflammatory characteristics and are distinct from those of DSS-treated control mice as well as myeloid-derived suppressor cells in tumor-bearing mice. Thus, our study reveals that the lack of WNT5 reprograms neutrophils in spleens to limit colonic injury during DSS-induced colitis.

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Ferroptosis of tumour neutrophils causes immune suppression in cancer

Cited by 198 publications

References 57 publications

The Emerging Role of Ferroptosis in Various Chronic Liver Diseases: Opportunity or Challenge

The Emerging Role of Ferroptosis in Various Chronic Liver Diseases: Opportunity or Challenge

BACH1-induced ferroptosis drives lymphatic metastasis by repressing the biosynthesis of monounsaturated fatty acids

Loss of WNT5 Proteins Reprograms Neutrophils in the Spleen to Provide Protection for DSS-Induced Colitis

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