PMN-MDSCs modulated by CCL20 from cancer cells promoted breast cancer cell stemness through CXCL2-CXCR2 pathway

Zhang, Rui; Dong, Ming; Tu, Juchuanli; Li, Fengkai; Deng, Qiaodan; Xu, Jiahui; He, Xueyan; Ding, Jiajun; Xia, Jie; Sheng, Dandan; Chang, Zhaoxia; Ma, Wei; Dong, Haonan; Zhang, Yi; Zhang, Lixing; Zhang, Lu; Liu, Suling

doi:10.1038/s41392-023-01337-3

Cited by 34 publications

(9 citation statements)

References 63 publications

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“…The dual potential of in macrophages cancer were recently well reviewed, reflecting their plasticity in response to environmental cues (41). In breast cancer, tumor-derived CCL20 has been recently reported to signal on CCR6 in precursor macrophages, promote PMN-MDSC expansion and exert pro-tumor effects (42). In osteosarcoma, complementassociated macrophages have been reported to mediate M1 polarization and antitumor immunity (43).…”

Section: Discussionmentioning

confidence: 99%

Proteasome-dependent senescent tumor cells mediate immunosuppression through CCL20 secretion and M2 polarization in pancreatic ductal adenocarcinoma

Han

et al. 2023

Front. Immunol.

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The outcome of pancreatic ductal adenocarcinoma (PDAC) remains poor due to few therapeutic options available and challenges with precision therapy to target each tumour’s specific characteristics. In this study, a biologically meaningful patient stratification-prognostic model with therapeutic suggestion value based on tumor senescence was developed and validated in multiple independent cohorts. Further mechanistic investigation based on single-cell transcriptomic data and in vitro experiments revealed that complement derived from non-senescent tumor cells stimulates M1 differentiation and antigen presentation, while senescent tumor cells secrete CCL20 to favor immunosuppressive M2 polarization. Also, senescent phenotype depends on proteasome function, suggesting that high-risk, high-senescence patients may benefit from proteasome inhibitors, which reverse senescence-mediated resistance to conventional chemotherapy and improve outcome. In conclusion, the current study identified senescence as a tumor-specific, hazardous factor associated with immunosuppression in PDAC. Mechanistically, senescence abrogates complement-induced M1 activation and antigen presentation, and upregulates CCL20 to favor M2 polarization. The senescence-related risk model is prognostic and therapeutic-suggestive. In light of the reliance of senescent cells on proteasomal functions, proteasome inhibitors are promising agents for high-risk patients with senescent PDAC.

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Section: Discussionmentioning

confidence: 99%

Proteasome-dependent senescent tumor cells mediate immunosuppression through CCL20 secretion and M2 polarization in pancreatic ductal adenocarcinoma

Han

et al. 2023

Front. Immunol.

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“…Additionally, CCL20 produced by breast cancer cells has been reported to modulate PMN-MDSC to promote cancer cell stemness through the CXCL2-CXCR2 pathway [163]. Moreover, tumor-secreted cytokines like CXCL8, PDGF, MIP1 and CSF3 increase the mobilization of neutrophils from the bone marrow and spleen, leading to an elevated neutrophilto-lymphocyte ratio in both human [156,[164][165][166] and mouse [22,167] studies.…”

Section: Effect Of Cytokines On Neutrophil and Pmn-mdsc Migrationmentioning

confidence: 99%

The Role of Cytokines in Neutrophil Development, Tissue Homing, Function and Plasticity in Health and Disease

Tsioumpekou,

Krijgsman,

Leusen

et al. 2023

Cells

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Neutrophils are crucial innate immune cells and comprise 50–70% of the white blood cell population under homeostatic conditions. Upon infection and in cancer, blood neutrophil numbers significantly increase because of the secretion of various chemo- and cytokines by, e.g., leukocytes, pericytes, fibroblasts and endothelial cells present in the inflamed tissue or in the tumor microenvironment (TME). The function of neutrophils in cancer has recently gained considerable attention, as they can exert both pro- and anti-tumorigenic functions, dependent on the cytokine milieu present in the TME. Here, we review the effect of cytokines on neutrophil development, tissue homing, function and plasticity in cancer and autoimmune diseases as well as under physiological conditions in the bone marrow, bloodstream and various organs like the spleen, kidney, liver, lung and lymph nodes. In addition, we address several promising therapeutic options, such as cytokine therapy, immunocytokines and immunotherapy, which aim to exploit the anti-tumorigenic potential of neutrophils in cancer treatment or block excessive neutrophil-mediated inflammation in autoimmune diseases.

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“…MDSCs from anti-Fgl2 treated MC38 tumors exhibited a reduction in cholesterol content compared with control tumors (figure 7H). The 4T1 breast tumor model, known for its high infiltration of MDSCs in the TME, [29][30][31][32] was also used in our study. As expected, we observed a comparable level of tumor inhibition in the group of mice treated with anti-Fgl2 (online supplemental figure S7C).…”

Section: Open Accessmentioning

confidence: 99%

Fibrinogen-like protein 2 promotes tumor immune suppression by regulating cholesterol metabolism in myeloid-derived suppressor cells

Wu,

Liu,

Lei

et al. 2023

J Immunother Cancer

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BackgroundMyeloid-derived suppressor cells (MDSCs) are crucial mediators of tumor-associated immune suppression. Targeting the accumulation and activation of MDSCs has been recognized as a promising approach to enhance the effectiveness of immunotherapies for different types of cancer.MethodsThe MC38 and B16 tumor-bearing mouse models were established to investigate the role of Fgl2 during tumor progression. Fgl2 and FcγRIIB-deficient mice, adoptive cell transfer, RNA-sequencing and flow cytometry analysis were used to assess the role of Fgl2 on immunosuppressive activity and differentiation of MDSCs.ResultsHere, we show that fibrinogen-like protein 2 (Fgl2) regulates the differentiation and immunosuppressive functions of MDSCs. The absence of Fgl2 leads to an increase in antitumor CD8+T-cell responses and a decrease in granulocytic MDSC accumulation. The regulation mechanism involves Fgl2 modulating cholesterol metabolism, which promotes the accumulation of MDSCs and immunosuppression through the production of reactive oxygen species and activation of XBP1 signaling. Inhibition of Fgl2 or cholesterol metabolism in MDSCs reduces their immunosuppressive activity and enhances differentiation. Targeting Fgl2 could potentially enhance the therapeutic efficacy of anti-PD-1 antibody in immunotherapy.ConclusionThese results suggest that Fgl2 plays a role in promoting immune suppression by modulating cholesterol metabolism and targeting Fgl2 combined with PD-1 checkpoint blockade provides a promising therapeutic strategy for antitumor therapy.

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PMN-MDSCs modulated by CCL20 from cancer cells promoted breast cancer cell stemness through CXCL2-CXCR2 pathway

Cited by 34 publications

References 63 publications

Proteasome-dependent senescent tumor cells mediate immunosuppression through CCL20 secretion and M2 polarization in pancreatic ductal adenocarcinoma

Proteasome-dependent senescent tumor cells mediate immunosuppression through CCL20 secretion and M2 polarization in pancreatic ductal adenocarcinoma

The Role of Cytokines in Neutrophil Development, Tissue Homing, Function and Plasticity in Health and Disease

Fibrinogen-like protein 2 promotes tumor immune suppression by regulating cholesterol metabolism in myeloid-derived suppressor cells

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