Neutrophils in Cancer: Two Sides of the Same Coin

Abstract

Neutrophils are the most abundant leukocytes in blood and are considered to be the first line of defense during inflammation and infections. In addition, neutrophils are also found infiltrating many types of tumors. Tumor-associated neutrophils (TANs) have relevant roles in malignant disease. Indeed neutrophils may be potent antitumor effector cells. However, increasing clinical evidence shows TANs correlate with poor prognosis. The tumor microenvironment controls neutrophil recruitment and in turn TANs help tumor progression. Hence, TANs can be beneficial or detrimental to the host. It is the purpose of this review to highlight these two sides of the neutrophil coin in cancer and to describe recent studies that provide some light on the mechanisms for neutrophil recruitment to the tumor, for neutrophils supporting tumor progression, and for neutrophil activation to enhance their antitumor functions.

Figure 1

Mechanisms of neutrophil recruitment to tumors. Tumor cells produce many chemokines, such as CXCL1 (KC), CXCL2 (MIP-2), CXCL5 (ENA-78), CXCL6 (GCP-2), CXCL8 (IL-8), and MIF, which are chemoattractants for neutrophils. These cells then migrate out of the blood circulation into the tumor. Tumor-associated neutrophils can also produce CCL17, an important chemoattractant for regulatory T cells (Treg). These inhibitory Treg in turn produce more IL-8, the most potent chemoattractant for neutrophils, creating a positive loop for more neutrophil infiltration into the growing tumor. Blue arrows denote molecules secreted by cells. Green arrows denote the action of molecules on cells. Dotted lines denote cell movement.

Figure 2

Protumor activity of neutrophils. Tumor-associated neutrophils (TANs) help tumor progression in several ways. TANs can secrete matrix metalloproteinase-9 (MMP-9) that releases vascular endothelial growth factor (VEGF) from the extracellular matrix (ECM) to promote angiogenesis. TAN can secrete cytokines (IL-1β, TNF-α, IL-6, and IL-12) that induce a chronic inflammatory state and arginase 1, which inhibits CD8 T cells, creating an immunosuppressive state. TANs also produce reactive oxygen species (ROS) that can damage DNA, inducing genotoxic effects on tumor cells. Serine proteases, such as elastase and cathepsin G, from neutrophil granules seem to have a direct effect on tumor cells for inducing proliferation. Certain tumors, like breast cancer cells, induce neutrophils to produce Oncostatin, an IL-6-like cytokine that then stimulates breast cancer cells to secrete vascular endothelial growth factor to promote angiogenesis (red lines represent new blood vessels). Also, hepatocellular carcinoma cells induce neutrophils to release hepatocyte growth factor (HGF), which activates tumor cells to become more invasive. Blue arrows denote molecules secreted by cells. Green arrows denote the action of molecules on cells.

Figure 3

Neutrophils can promote tumor cell invasion and metastasis. Tumor-associated neutrophils (TANs) help tumor invasion in several ways. TANs can secrete enzymes, such as elastase (red dots), that degrade the basement membrane and promote tumor cell invasion through the basement membrane. Once in circulation, neutrophils can also help tumor cells to survive by inducing tumor cell aggregation. Circulating tumor cells can directly adhere to arrested neutrophils via the adhesion molecule ICAM-1 on the tumor cells, and β2 integrins on neutrophils. This cell-cell interaction promotes extravasation of the tumor cells. Bone marrow-derived cells including neutrophil precursors (Gr-1⁺CD11b⁺ cells) migrate to premetastatic niches where they secrete factors that promote tumor cell growth. Blue arrows denote molecules secreted by cells. Dotted lines denote cell movement.

Figure 4

Antitumor activity of neutrophils. Neutrophils produce reactive oxygen species (ROS) and hypochlorous acid (HOCl) that can directly damage and destroy tumor cells. By direct contact or by release of TRAIL, neutrophils can also induce apoptosis of certain tumor cells. The most effective antitumor mechanism is antibody-dependent cell-mediated cytotoxicity (ADCC). Antibody molecules (green) that bind to tumor antigens are recognized by Fc receptors (orange circles) on neutrophils. This binding activates a cytotoxic response against the tumor cell. Neutrophils can be activated to display a stronger antitumor phenotype with granulocyte colony-stimulating factor (G-CSF), transforming growth factor-α (TNF-α), or by blocking (red cross) transforming growth factor-β (TGF-β). Also, the blockage of IL-8, with specific monoclonal antibodies (such as mAb ABX-IL8), can prevent new neutrophil infiltration into growing tumors. Inflammatory neutrophils can also activate cytotoxic (CD8) T cells. All these mechanisms result in smaller tumors. Blue arrows denote molecules secreted by cells. Green arrows denote the action of molecules on cells.

Figure 5

Neutrophil extracellular traps (NETs) can induce tumor progression. Tumor-associated neutrophils can produce NETs (blue lines), which are chromatin fibers decorated with proteins from neutrophil granules (red circles). (a) Tumor cells trapped in these NETs would get exposed to high local concentrations of neutrophil elastase and other factors that induce cell proliferation. (b) NETs could also provide large amounts of matrix metalloproteinase-9 and serine proteases that would release vascular endothelial growth factor to promote angiogenesis. (c) NETs released on the vascular endothelium in response to inflammation could trap tumor cells allowing them to more easily arrest and extravasate the blood circulation into prometastatic sites.