Neutrophils resist ferroptosis and promote breast cancer metastasis through aconitate decarboxylase 1

Yun Zhao; Zhongshun Liu; Guoqiang Liu; Yuting Zhang; Sheng Liu; Dailin Gan; Wennan Chang; Xiaoxia Peng; Eun Suh Sung; Keegan Gilbert; Yini Zhu; Xuechun Wang; Ziyu Zeng; Hope Baldwin; Guanzhu Ren; Jessica Weaver; Anna Huron; Toni Mayberry; Qingfei Wang; Yujue Wang; Maria Elena Diaz-Rubio; Xiaoyang Su; M. Sharon Stack; Siyuan Zhang; Xuemin Lu; Ryan D. Sheldon; Jun Li; Chi Zhang; Jun Wan; Xin Lu

doi:10.1016/j.cmet.2023.09.004

Neutrophils resist ferroptosis and promote breast cancer metastasis through aconitate decarboxylase 1

Yun Zhao, Zhongshun Liu, Guoqiang Liu, Yuting Zhang, Sheng Liu, Dailin Gan, Wennan Chang, Xiaoxia Peng, Eun Suh Sung, Keegan Gilbert, Yini Zhu, Xuechun Wang, Ziyu Zeng, Hope Baldwin, Guanzhu Ren, Jessica Weaver, Anna Huron, Toni Mayberry, Qingfei Wang, Yujue WangMaria Elena Diaz-Rubio, Xiaoyang Su, M. Sharon Stack, Siyuan Zhang, Xuemin Lu, Ryan D. Sheldon, Jun Li, Chi Zhang, Jun Wan, Xin Lu

Research output: Contribution to journal › Article › peer-review

16 Scopus citations

Abstract

Metastasis causes breast cancer-related mortality. Tumor-infiltrating neutrophils (TINs) inflict immunosuppression and promote metastasis. Therapeutic debilitation of TINs may enhance immunotherapy, yet it remains a challenge to identify therapeutic targets highly expressed and functionally essential in TINs but under-expressed in extra-tumoral neutrophils. Here, using single-cell RNA sequencing to compare TINs and circulating neutrophils in murine mammary tumor models, we identified aconitate decarboxylase 1 (Acod1) as the most upregulated metabolic enzyme in mouse TINs and validated high Acod1 expression in human TINs. Activated through the GM-CSF-JAK/STAT5-C/EBPβ pathway, Acod1 produces itaconate, which mediates Nrf2-dependent defense against ferroptosis and upholds the persistence of TINs. Acod1 ablation abates TIN infiltration, constrains metastasis (but not primary tumors), bolsters antitumor T cell immunity, and boosts the efficacy of immune checkpoint blockade. Our findings reveal how TINs escape from ferroptosis through the Acod1-dependent immunometabolism switch and establish Acod1 as a target to offset immunosuppression and improve immunotherapy against metastasis.

Original language	English (US)
Pages (from-to)	1688-1703.e10
Journal	Cell Metabolism
Volume	35
Issue number	10
DOIs	https://doi.org/10.1016/j.cmet.2023.09.004
State	Published - Oct 3 2023

Keywords

Acod1
MDSC
breast cancer
ferroptosis
immune checkpoint blockade
immune metabolism
itaconate
metastasis
neutrophil
single-cell RNA sequencing

ASJC Scopus subject areas

Physiology
Molecular Biology
Cell Biology

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10.1016/j.cmet.2023.09.004

Cite this

Zhao, Y., Liu, Z., Liu, G., Zhang, Y., Liu, S., Gan, D., Chang, W., Peng, X., Sung, E. S., Gilbert, K., Zhu, Y., Wang, X., Zeng, Z., Baldwin, H., Ren, G., Weaver, J., Huron, A., Mayberry, T., Wang, Q., ... Lu, X. (2023). Neutrophils resist ferroptosis and promote breast cancer metastasis through aconitate decarboxylase 1. Cell Metabolism, 35(10), 1688-1703.e10. https://doi.org/10.1016/j.cmet.2023.09.004

Zhao, Y, Liu, Z, Liu, G, Zhang, Y, Liu, S, Gan, D, Chang, W, Peng, X, Sung, ES, Gilbert, K, Zhu, Y, Wang, X, Zeng, Z, Baldwin, H, Ren, G, Weaver, J, Huron, A, Mayberry, T, Wang, Q, Wang, Y, Diaz-Rubio, ME, Su, X, Stack, MS, Zhang, S, Lu, X, Sheldon, RD, Li, J, Zhang, C, Wan, J & Lu, X 2023, 'Neutrophils resist ferroptosis and promote breast cancer metastasis through aconitate decarboxylase 1', Cell Metabolism, vol. 35, no. 10, pp. 1688-1703.e10. https://doi.org/10.1016/j.cmet.2023.09.004

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title = "Neutrophils resist ferroptosis and promote breast cancer metastasis through aconitate decarboxylase 1",

abstract = "Metastasis causes breast cancer-related mortality. Tumor-infiltrating neutrophils (TINs) inflict immunosuppression and promote metastasis. Therapeutic debilitation of TINs may enhance immunotherapy, yet it remains a challenge to identify therapeutic targets highly expressed and functionally essential in TINs but under-expressed in extra-tumoral neutrophils. Here, using single-cell RNA sequencing to compare TINs and circulating neutrophils in murine mammary tumor models, we identified aconitate decarboxylase 1 (Acod1) as the most upregulated metabolic enzyme in mouse TINs and validated high Acod1 expression in human TINs. Activated through the GM-CSF-JAK/STAT5-C/EBPβ pathway, Acod1 produces itaconate, which mediates Nrf2-dependent defense against ferroptosis and upholds the persistence of TINs. Acod1 ablation abates TIN infiltration, constrains metastasis (but not primary tumors), bolsters antitumor T cell immunity, and boosts the efficacy of immune checkpoint blockade. Our findings reveal how TINs escape from ferroptosis through the Acod1-dependent immunometabolism switch and establish Acod1 as a target to offset immunosuppression and improve immunotherapy against metastasis.",

keywords = "Acod1, MDSC, breast cancer, ferroptosis, immune checkpoint blockade, immune metabolism, itaconate, metastasis, neutrophil, single-cell RNA sequencing",

author = "Yun Zhao and Zhongshun Liu and Guoqiang Liu and Yuting Zhang and Sheng Liu and Dailin Gan and Wennan Chang and Xiaoxia Peng and Sung, {Eun Suh} and Keegan Gilbert and Yini Zhu and Xuechun Wang and Ziyu Zeng and Hope Baldwin and Guanzhu Ren and Jessica Weaver and Anna Huron and Toni Mayberry and Qingfei Wang and Yujue Wang and Diaz-Rubio, {Maria Elena} and Xiaoyang Su and Stack, {M. Sharon} and Siyuan Zhang and Xuemin Lu and Sheldon, {Ryan D.} and Jun Li and Chi Zhang and Jun Wan and Xin Lu",

note = "Publisher Copyright: {\textcopyright} 2023 Elsevier Inc.",

year = "2023",

month = oct,

day = "3",

doi = "10.1016/j.cmet.2023.09.004",

language = "English (US)",

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T1 - Neutrophils resist ferroptosis and promote breast cancer metastasis through aconitate decarboxylase 1

AU - Zhao, Yun

AU - Liu, Zhongshun

AU - Liu, Guoqiang

AU - Zhang, Yuting

AU - Liu, Sheng

AU - Gan, Dailin

AU - Chang, Wennan

AU - Peng, Xiaoxia

AU - Sung, Eun Suh

AU - Gilbert, Keegan

AU - Zhu, Yini

AU - Wang, Xuechun

AU - Zeng, Ziyu

AU - Baldwin, Hope

AU - Ren, Guanzhu

AU - Weaver, Jessica

AU - Huron, Anna

AU - Mayberry, Toni

AU - Wang, Qingfei

AU - Wang, Yujue

AU - Diaz-Rubio, Maria Elena

AU - Su, Xiaoyang

AU - Stack, M. Sharon

AU - Zhang, Siyuan

AU - Lu, Xuemin

AU - Sheldon, Ryan D.

AU - Li, Jun

AU - Zhang, Chi

AU - Wan, Jun

AU - Lu, Xin

PY - 2023/10/3

Y1 - 2023/10/3

N2 - Metastasis causes breast cancer-related mortality. Tumor-infiltrating neutrophils (TINs) inflict immunosuppression and promote metastasis. Therapeutic debilitation of TINs may enhance immunotherapy, yet it remains a challenge to identify therapeutic targets highly expressed and functionally essential in TINs but under-expressed in extra-tumoral neutrophils. Here, using single-cell RNA sequencing to compare TINs and circulating neutrophils in murine mammary tumor models, we identified aconitate decarboxylase 1 (Acod1) as the most upregulated metabolic enzyme in mouse TINs and validated high Acod1 expression in human TINs. Activated through the GM-CSF-JAK/STAT5-C/EBPβ pathway, Acod1 produces itaconate, which mediates Nrf2-dependent defense against ferroptosis and upholds the persistence of TINs. Acod1 ablation abates TIN infiltration, constrains metastasis (but not primary tumors), bolsters antitumor T cell immunity, and boosts the efficacy of immune checkpoint blockade. Our findings reveal how TINs escape from ferroptosis through the Acod1-dependent immunometabolism switch and establish Acod1 as a target to offset immunosuppression and improve immunotherapy against metastasis.

AB - Metastasis causes breast cancer-related mortality. Tumor-infiltrating neutrophils (TINs) inflict immunosuppression and promote metastasis. Therapeutic debilitation of TINs may enhance immunotherapy, yet it remains a challenge to identify therapeutic targets highly expressed and functionally essential in TINs but under-expressed in extra-tumoral neutrophils. Here, using single-cell RNA sequencing to compare TINs and circulating neutrophils in murine mammary tumor models, we identified aconitate decarboxylase 1 (Acod1) as the most upregulated metabolic enzyme in mouse TINs and validated high Acod1 expression in human TINs. Activated through the GM-CSF-JAK/STAT5-C/EBPβ pathway, Acod1 produces itaconate, which mediates Nrf2-dependent defense against ferroptosis and upholds the persistence of TINs. Acod1 ablation abates TIN infiltration, constrains metastasis (but not primary tumors), bolsters antitumor T cell immunity, and boosts the efficacy of immune checkpoint blockade. Our findings reveal how TINs escape from ferroptosis through the Acod1-dependent immunometabolism switch and establish Acod1 as a target to offset immunosuppression and improve immunotherapy against metastasis.

KW - Acod1

KW - MDSC

KW - breast cancer

KW - ferroptosis

KW - immune checkpoint blockade

KW - immune metabolism

KW - itaconate

KW - metastasis

KW - neutrophil

KW - single-cell RNA sequencing

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U2 - 10.1016/j.cmet.2023.09.004

DO - 10.1016/j.cmet.2023.09.004

M3 - Article

C2 - 37793345

AN - SCOPUS:85172702243

SN - 1550-4131

VL - 35

SP - 1688-1703.e10

JO - Cell Metabolism

JF - Cell Metabolism

IS - 10

ER -

Neutrophils resist ferroptosis and promote breast cancer metastasis through aconitate decarboxylase 1

Abstract

Keywords

ASJC Scopus subject areas

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