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Review
. 2020 Sep 24:11:565165.
doi: 10.3389/fimmu.2020.565165. eCollection 2020.

Neutrophil: A New Player in Metastatic Cancers

Mengyue Wu  1 , Mutian Ma  1 , Zhenya Tan  1 , Hong Zheng  1 , Xia Liu  2
Affiliations
Review

Neutrophil: A New Player in Metastatic Cancers

Mengyue Wu et al. Front Immunol. .

Abstract

The interaction between cancer cells and immune cells is important for the cancer development. However, much attention has been given to T cells and macrophages. Being the most abundant leukocytes in the blood, the functions of neutrophils in cancer have been underdetermined. They have long been considered an "audience" in the development of cancer. However, emerging evidence indicate that neutrophils are a heterogeneous population with plasticity, and subpopulation of neutrophils (such as low density neutrophils, polymorphonuclear-myeloid-derived suppressor cells) are actively involved in cancer growth and metastasis. Here, we review the current understanding of the role of neutrophils in cancer development, with a specific focus on their pro-metastatic functions. We also discuss the potential and challenges of neutrophils as therapeutic targets. A better understanding the role of neutrophils in cancer will discover new mechanisms of metastasis and develop new immunotherapies by targeting neutrophils.

Keywords: circulating tumor cells; immunosuppression; metastasis; neutrophils; pre-metastatic niche; tumor microenvironments.

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Figures

Figure 1
Figure 1
The role of neutrophils in TME. (A) γδ17 T cells which secret IL-17 can recruit neutrophils into TME to stimulate the angiogenesis by producing VEGF and MMP9. In addition, γδ17 T cells can produce G-CSF to expand, and polarize neutrophils to promote metastasis by suppressing cytotoxic CD8 T cells immunity. (B) eIF4E is phosphorylated by MNK1/2 to promote neutrophils survival and accumulation in TME due to increased expression of BCL2 and MCL1, which then promote metastasis. (C) Estradiol (E2) promotes N2 polarization of neutrophils via TGF-β1, thus causing cancer cells to be highly metastatic. (D) TNFα-activated MSCs promote metastasis via production of CXCL1, CXCL2, and CXCL5 to recruit CXCR2+ neutrophils, and then neutrophils activate tumor cells to express higher levels of metastasis-related genes including CXCR4, CXCR7, MMP12, MMP13, IL-6 and TGFβ. In addition, tumor cells secreted GM-CSF can induce neutrophils to produce HGF, which binds to c-Met on tumor cells to promote metastasis. (E) Tumor-derived GM-CSF induces PD-L1 expression on neutrophil via JAK-STAT3signaling pathway, and cancer-associated fibroblasts (CAFs) induce PD-L1 expression on neutrophils by IL6—STAT3 signaling pathway, both of which inhibit T-cell immunity. In addition, c-Kit+ neutrophils use fatty acid oxidative metabolism to support ROS production to mediate T cell suppression.
Figure 2
Figure 2
Neutrophils interact with CTCs to promote metastasis. CTC-associated neutrophils express VCAM-1 to mediate their interaction, and produce IL-1β and IL-6 to support CTC proliferation, leading to enhanced metastatic potential of CTC clusters. Both CTC clusters and neutrophil-CTC clusters can prevent CTCs from being killed by NK cells and T cells. In addition, β1-integrin mediated interactions between CTCs and NETs can trap CTCs, thereby promoting adhesion of CTCs to distant organs and metastasis.
Figure 3
Figure 3
Neutrophils facilitate CTCs extravasation. E/P-selectin on the endothelial cell mediates the initial attachment and rolling of neutrophils along the endothelial surface. Then neutrophils capture tumor cells via LFA-1 and ICAM-1 interactions. LFA-1 on neutrophils also bind to ICAM-1 on the endothelial cells to arrest and activate neutrophils. After arrest, neutrophils within clusters are highly migratory mediated by neutrophils self-secreted IL-8 and tumor-derived CXCL-1. On the other hand, tumor cell secreted IL-8 increases Mac-1 expression on neutrophils to promote their binding to ICAM-1 on endothelial cells, and also prolong interaction with CTCs via Mac-1-mediated interactions with ICAM-1-expressing CTCs. Neutrophils can also facilitate CTCs adhesion to endothelium, which is dependent on selectin ligands containing sialyl-Lewis x (sLex) moieties on the surface of the tumor cells and E-selectin on endothelial cells. Together, neutrophils increase the extravasation potential of nearby entrapped tumor cells through disruption of the endothelial barrier.
Figure 4
Figure 4
The role of neutrophils in pre-metastatic niche. Primary tumor cells secret various cytokines, chemokines, and signals to recruit neutrophils to distant organs to form pre-metastatic niche. For example, tumor cell secreted-IL-8, MCP-1, GROα, GROβ, and G-CSF can mobilize neutrophils to the pre-metastatic niche, which then facilitate colonization of tumor cells and subsequent metastasis; GM-CSF produced by tumor cells can induce transferrin synthesis in neutrophils through the Jak/Stat5β pathway; TIMP-1 increases SDF1 levels, which in turn promote recruitment of neutrophils to the liver to promote liver metastasis; tumor exosomal RNAs activate TLR3 to induce chemokines that are critical for neutrophil recruitment and lung pre-metastatic niche formation. At pre-metastatic niche, activated neutrophils produce IL-1β, TNF-α, IL-6, and Cox-2, and degranulate azurophilic granules to release elastase and cathepsin G, leading to degradation of the Tsp-1 and enhanced metastasis. In addition, neutrophils support metastatic lung colonization via ALOX5-dependent leukotriene (LT) synthesis/release.
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