Lactoferrin deficiency induces a pro-metastatic tumor microenvironment through recruiting myeloid-derived suppressor cells in mice

Wei, Lingyu; Zhang, Xuemei; Wang, Jia; Ye, Qiurong; Zheng, Xiang; Qiu, Ping; Zheng, Ying; Liu, Peishan; Zhang, Xiaoyue; Li, Zhengshuo; Liu, Can; Yan, Qun; Li, Guiyuan; Ma, Jian

doi:10.1038/s41388-019-0970-8

Cited by 21 publications

(16 citation statements)

References 77 publications

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“…Direct antitumor effects of LTF and its derivatives have previously been reported, including inhibition of cancer cell proliferation, cell cycle arrest and facilitation of cancer cell apoptosis or necrosis. [30][31][32][33][34] In our study, however, neither LTF alone nor LTF-IC showed direct antitumor effects in terms of proliferation inhibition (online supplementary figure S2) or specific lysis (figure 4A) of tumor cells. One possible explanation for this discrepancy is the huge variation of LTF concentrations employed by different groups.…”

Section: Open Accesscontrasting

confidence: 75%

“…29 Lactoferrin (LTF), first identified as an iron-binding protein, exerts diverse biological functions including antitumor effects. [30][31][32][33][34] M860 is a mouse antihuman LTF monoclonal antibody (mAb), prepared in this laboratory, which recognizes a conformation epitope and is able to form stable immunocomplex (IC) with LTF. 32 35 We have also shown that LTF-containing IC (LTF-IC) is able to switch human macrophages from M2 to M1 phenotype.…”

Section: Introductionmentioning

confidence: 99%

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Lactoferrin-containing immunocomplex mediates antitumor effects by resetting tumor-associated macrophages to M1 phenotype

Dong

Yang

Gao

et al. 2020

J Immunother Cancer

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BackgroundTumor-associated macrophages (TAMs) resemble M2-polarized cells with potent immunosuppressive activity and play a pivotal role in tumor growth and progression. Converting TAMs to proinflammatory M1-like phenotype is thus an attractive strategy for antitumor immunotherapy.MethodsA mouse IgG1(kappa) monoclonal Ab, M-860, specific to human lactoferrin (LTF) was generated by using the traditional hybridoma cell fusion technology. TAMs were generated by culturing human and mouse CD14+monocytes in tumor-conditioned media containing a cytokine cocktail containing recombinant interleukin-4 (IL-4), interleukin-10 (IL-10) and macrophage colony stimulating factor (M-CSF). TAMs after treatment with immunocomplex (IC) between human LTF and M860 (LTF-IC) were phenotypically and functionally characterized by flow cytometry (FACS), ELISA, Q-PCR and killing assays. The antitumor effects of LTF-IC were further analyzed using in vivo experiments employing tumor-bearing human FcγRIIa-transgenic mouse models.ResultsThrough coligation of membrane-bound CD14 and FcγRIIa, LTF-IC rendered TAMs not only M2 to M1 conversion, evidenced by increased tumor necrosis factor α production, down-regulated M2-specific markers (CD206, arginase-1 and vascular endothelial growth factor) and upregulated M1-specific markers (CD86 and HLA-DR) expression, but also potent tumoricidal activity in vitro. LTF-IC administration conferred antitumor protective efficacy and prolonged animal survival in FcγRIIa-transgenic mice, accompanied by accumulation of M1-like macrophages as well as significantly reduced infiltration of immunosuppressive myeloid-derived suppressor cells and regulatory T cells in solid tumor tissues.ConclusionsLTF-IC is a promising cancer therapeutic agent capable of converting TAMs into tumoricidal M1-like cells.

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Section: Open Accesscontrasting

confidence: 75%

Section: Introductionmentioning

confidence: 99%

Lactoferrin-containing immunocomplex mediates antitumor effects by resetting tumor-associated macrophages to M1 phenotype

Dong

Yang

Gao

et al. 2020

J Immunother Cancer

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“…A recent study has shown enhanced MDSC recruitment into the pre-metastatic site in the lung in a lactoferrin-knockout mice model, which subsequently leads to significant metastasis of melanoma cells. In this model, TLR9 signaling in MDSC is remarkably attenuated, indicating one possible lactoferrin-TLR9 signaling axis in MDSC that regulates their migration to pre-metastatic organs [ 98 ]. Expression of MM9 and IL-1β from MDSC in the pre-metastatic niche of lungs has a key role in attracting circulating cancer cells [ 99 , 100 ].…”

Section: Mdsc In Tumor Microenvironmentmentioning

confidence: 99%

Landscape of Myeloid-derived Suppressor Cell in Tumor Immunotherapy

Hao

Wang

et al. 2021

Biomark Res

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Myeloid-derived suppressor cells (MDSC) are a group of immature cells that produced by emergency myelopoiesis. Emerging evidences have identified the vital role of MDSC in cancer microenvironment, in which MDSC exerts both immunological and non-immunological activities to assist the progression of cancer. Advances in pre-clinical research have provided us the understanding of MDSC in cancer context from the perspective of molecular mechanism. In clinical scenario, MDSC and its subsets have been discovered to exist in peripheral blood and tumor site of patients from various types of cancers. In this review, we highlight the clinical value of MDSC in predicting prognosis of cancer patients and the responses of immunotherapies, therefore to propose the MDSC-inhibiting strategy in the scenario of cancer immunotherapies. Phenotypes and biological functions of MDSC in cancer microenvironment are comprehensively summarized to provide potential targets of MDSC-inhibiting strategy from the aspect of molecular mechanisms.

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“…As described above, in 1994 Bazault and colleagues reported the first evidence for the anti-metastatic effect of Lf in rat models [102]. Since then, several studies have reported the Lf anti-metastatic ability against other types of cancers [87,88,181,182]. In particular, subcutaneous administration of apo-bLf and Lfcin-B in mice inoculated with two different cancer cell lines, B16-BL6 melanoma and L5178Y-ML25 lymphoma cells, resulted in significant inhibition of liver and spleen metastasis for L5178Y-ML25 cells and lung metastasis for B16-BL6 cells, as well as of tumor-induced blood vessel formation [181].…”

Section: Lactoferrin Anti-cancer Activity: Inhibition Of Cell Migratimentioning

confidence: 99%

“…Recently, Wei and colleagues demonstrated that Lf deficiency enhanced melanoma metastasizing to lungs in an Lf KO mouse model by recruiting myeloid derived suppressor cells (MDSCs). Molecular studies showed that TLR9 signaling, negatively involved in MDSC-mediated cancer metastasis, was highly repressed and that exogenous Lf administration was able to revert the phenotype by enhancing TLR9 pathway as well as by inducing MDSCs differentiation and apoptosis [182].…”

Section: Lactoferrin Anti-cancer Activity: Inhibition Of Cell Migratimentioning

confidence: 99%

Lactoferrin’s Anti-Cancer Properties: Safety, Selectivity, and Wide Range of Action

et al. 2020

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Despite recent advances in cancer therapy, current treatments, including radiotherapy, chemotherapy, and immunotherapy, although beneficial, present attendant side effects and long-term sequelae, usually more or less affecting quality of life of the patients. Indeed, except for most of the immunotherapeutic agents, the complete lack of selectivity between normal and cancer cells for radioand chemotherapy can make them potential antagonists of the host anti-cancer self-defense over time. Recently, the use of nutraceuticals as natural compounds corroborating anti-cancer standard therapy is emerging as a promising tool for their relative abundance, bioavailability, safety, low-cost effectiveness, and immuno-compatibility with the host. In this review, we outlined the anti-cancer properties of Lactoferrin (Lf), an iron-binding glycoprotein of the innate immune defense. Lf shows high bioavailability after oral administration, high selectivity toward cancer cells, and a wide range of molecular targets controlling tumor proliferation, survival, migration, invasion, and metastasization. Of note, Lf is able to promote or inhibit cell proliferation and migration depending on whether it acts upon normal or cancerous cells, respectively. Importantly, Lf administration is highly tolerated and does not present significant adverse effects. Moreover, Lf can prevent development or inhibit cancer growth by boosting adaptive immune response. Finally, Lf was recently found to be an ideal carrier for chemotherapeutics, even for the treatment of brain tumors due to its ability to cross the blood-brain barrier, thus globally appearing as a promising tool for cancer prevention and treatment, especially in combination therapies.

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Lactoferrin deficiency induces a pro-metastatic tumor microenvironment through recruiting myeloid-derived suppressor cells in mice

Cited by 21 publications

References 77 publications

Lactoferrin-containing immunocomplex mediates antitumor effects by resetting tumor-associated macrophages to M1 phenotype

Lactoferrin-containing immunocomplex mediates antitumor effects by resetting tumor-associated macrophages to M1 phenotype

Landscape of Myeloid-derived Suppressor Cell in Tumor Immunotherapy

Lactoferrin’s Anti-Cancer Properties: Safety, Selectivity, and Wide Range of Action

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