Neutrophils with protumor potential could efficiently suppress tumor growth after cytokine priming and in presence of normal NK cells

Sun, Rui; Luo, Jing; Liu, Dong; Shu, Yu; Luo, Chao; Wang, Shanshan; Qin, Jian; Zhang, Guimei; Feng, Zuo-Hua

doi:10.18632/oncotarget.2181

Cited by 38 publications

(27 citation statements)

References 53 publications

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“…Human NK cells trigger neutrophil apoptosis through activating NK-cell receptor NKp46-and Fas-dependent pathways (47,48). The NK cell-produced cytokines, IFNg and TNFa, convert neutrophils from tumor promoting to tumor suppressing (49). TANs also influence tumor control by coordinating with other components of immune cells through their ability to suppress antitumor immunity (43,50,51).…”

Section: Discussionmentioning

confidence: 99%

NK Cells Control Tumor-Promoting Function of Neutrophils in Mice

Ogura

Sato-Matsushita

Yamamoto

et al. 2018

Cancer Immunology Research

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Although natural killer (NK) cells are recognized as direct antitumor effectors, the ability of NK cells to control cancer-associated inflammation, which facilitates tumor progression, remains unknown. In this study, we demonstrate that NK cells control tumor-promoting inflammation through functional modification of neutrophils. NK cells control the tumor-promoting function of neutrophils through an IFNγ-dependent mechanism. Tumor progression in an NK cell-depleted host is diminished when the IL17A-neutrophil axis is absent. In NK cell-depleted mice, neutrophils acquire a tumor-promoting phenotype, characterized by upregulation of VEGF-A expression, which promotes tumor growth and angiogenesis. A VEGFR inhibitor which preferentially suppressed tumor growth in NK cell-depleted mice was dependent on neutrophils. Furthermore, the systemic neutropenia caused by an antimetabolite treatment showed an anticancer effect only in mice lacking NK cells. Thus, NK cells likely control the tumor-promoting and angiogenic function of neutrophils.

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Section: Discussionmentioning

confidence: 99%

NK Cells Control Tumor-Promoting Function of Neutrophils in Mice

Ogura

Sato-Matsushita

Yamamoto

et al. 2018

Cancer Immunology Research

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“…The consequences of IFN stimulation on neutrophil function were multifold: IFNs were found to suppress the pro-angiogenic activity of neutrophils [ 23 ], regulate neutrophil recruitment and life-span in the primary tumor [ 28 , 29 ] and suppress the metastasis promoting activity of neutrophils in the pre-metastatic niche [ 6 ]. Similarly, TNFα was shown to limit tumor growth independently as well as though activation of anti-tumor immunity in neutrophils [ 30 ].…”

Section: Neutrophil Development and Regulation Of Their Bone Marrow Rmentioning

confidence: 99%

The regulation of pre-metastatic niche formation by neutrophils

Jabłońska

Lang

Sionov³

et al. 2017

Oncotarget

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Metastasis is a multistep process requiring tumor cell detachment from the primary tumor and migration to target organs through the lymphatic or blood circulatory systems. Specific organs are predisposed to metastases in certain cancers and the formation of supportive metastatic microenvironment determines tumor cell homing. Such an environment is provided by a pre-metastatic niche that is formed through the recruitment of bone marrow-derived myeloid cells, however the mechanisms of its formation are not fully understood. Recent evidence suggests that the primary tumor itself modulates the environment of secondary organs prior to tumor cell dissemination. The contribution of neutrophils to the formation of the pre-metastatic niche is getting growing attention. Obviously, neutrophils can affect the development of metastasis in two contradicting ways, by either stimulation or inhibition of this process, depending on the activation status. Pro-tumor neutrophils actively support metastasis formation by different mechanisms, including the formation of pre-metastatic niche, tumor cell attraction, and the direct support of tumor cell proliferation. Moreover, suppressive neutrophils, which are the granulocytic arm of MDSC, promote tumor progression by dampening anti-tumor T cell immunity. On the other hand, anti-tumor neutrophils can inhibit metastasis formation by the cytotoxicity towards tumor cells in the circulation or at the pre-metastatic site, and even via stimulation of T cell proliferation. Apparently, the regulation of the pro- or anti-tumor neutrophil properties has significant implications on metastatic spread in the host. Here we provide an up to date overview of the different roles neutrophils play in regulating the metastatic processes.

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“…TANs, the double-edged sword of innate immunity, are thus capable of being pro- or anti-tumorigenic depending on the tumor microenvironment [ 6 , 7 ]. Previous reports from our laboratory and others have shown that the inflammatory factors G-CSF/IL-6 [ 8 ] induce tumor-promoting neutrophils, while other mediators such as TNF-α and IFN-γ [ 9 ] or TGF-β blockade reverse the tumor-promoting effects of neutrophils [ 6 ], resulting in the recruitment and activation of TANs with an antitumor phenotype.…”

Section: Introductionmentioning

confidence: 99%

Tumor-associated neutrophils suppress antitumor immunity of NK cells through the PD-L1/PD-1 axis

Sun

Xiong

Liu

et al. 2020

Translational Oncology

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Studies have begun to emerge showing the protumor effects of tumor-associated neutrophils (TANs) in tumorigenesis, which may involve dysfunction of NK cells. However, the mechanism through which these rebellious neutrophils modulate NK cell immunity in tumor-bearing state remains unclear. In the present study, we demonstrate that neutrophils can impair the cytotoxicity and infiltration capability of NK cells, and downregulate CCR1 resulting in the weakened infiltration capability of NK cells. Moreover, neutrophils can decrease the responsiveness of NK-activating receptors, NKp46 and NKG2D. Mechanistically, enhanced PD-L1 on neutrophils and PD-1 on NK cells, and subsequent PD-L1/PD-1 interactions were the main mechanisms determining the suppression of neutrophils in NK cell immunity. G-CSF/STAT3 pathway was responsible for PD-L1 upregulation on neutrophils, while IL-18 was essential for PD-1 enhancement on NK cells. The crosstalk between neutrophils and NK cells was cell-cell interaction-dependent. These findings suggest that neutrophils can suppress the antitumor immunity of NK cells in tumor-bearing status through the PD-L1/PD-1 axis, highlighting the importance of PD-L1/PD-1 in the inhibitory effect of neutrophils on NK cells. Targeting G-CSF/STAT3 and IL-18 signaling pathway may be potential strategies to inhibit residual tumor in tumor therapy.

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Neutrophils with protumor potential could efficiently suppress tumor growth after cytokine priming and in presence of normal NK cells

Cited by 38 publications

References 53 publications

NK Cells Control Tumor-Promoting Function of Neutrophils in Mice

NK Cells Control Tumor-Promoting Function of Neutrophils in Mice

The regulation of pre-metastatic niche formation by neutrophils

Tumor-associated neutrophils suppress antitumor immunity of NK cells through the PD-L1/PD-1 axis

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