Potential pro- and anti-tumor functions of tumor-associated neutrophils (TANs). (IMAGE)
Caption
Potential pro- and anti-tumor functions of tumor-associated neutrophils (TANs). TANs may either promote or inhibit tumorigenesis and tumor progression through various immune mechanisms. (Figure left) Anti-tumor roles of TANs, which involve direct tumor cytotoxicity through secretion of protease granules, like reactive oxygen species (ROS) and myeloperoxidase (MPO). Additionally, TANs mediate the antibody-dependent cell-mediated cytotoxicity (ADCC) effect, facilitated by Fc receptors (FcR) on the surfaces, then activate and recruit other immune effector cells, leading to the elimination of antibody-targeted tumor cells by TANs. Apart from ADCC, TANs can further enhance the immune response. Dendritic cells, macrophages, and T cells secrete reactive cytokines within the TME, such as IL-12, TNF-α, and GM-CSF, which induce proliferation, maturation, and migration of TANs. TANs sequentially secrete C-C motif chemokine ligand 3 (CCL3), C-X-C motif chemokine ligand 9 (CXCL9), and CXCL10 that attract and recruit T cells, especially Th1 suppressing tumors to the TME. This coordinated action between TANs and other immune cells via cytokines and chemokines enhances the anti-tumor immune response. Overall, this dynamic interaction occurs predominantly in the early stage and is marked by a shorter cell lifespan and higher cell density. (Figure right) Pro-tumor roles of TANs in different aspects. TANs release abundant vascular endothelial growth factor-α (VEGF-α) and matrix metalloproteinase 9 (MMP-9), promoting angiogenesis and an increased blood supply, and a boost of tumor growth. In addition, enzymes, like elastases, MMP-8, MMP-9, cathepsin G, and proteinas-3 secreted by TANs, degrade the extracellular matrix and physical barrier facilitating tumor cell invasion into surrounding tissue. Moreover, TANs have an important role in promoting tumor proliferation in the late stage via secretion of neutrophil elastase (NE). Similarly, TANs have a negative effect on the immune system. Tumor necrosis factor-α (TNF-α), nitric oxide (NO), and arginase 1 (Arg-1) secreted by TANs and macrophage-1 Ag (Mac-1) and PD-L1 expressed on TANs suppress the immune response and enable tumors to escape the immune surveillance. CCL17 and CCL2 separately attract immune suppressive cells, like Tregs and myeloid-derived suppressor cells (MDSCs), leading to a favorably immune-deficient niche for tumors. In summary, TANs can also impair the anti-tumor immunity with a longer lifespan but lower cell density in the later stage of tumor progression. Notably, neutrophils in the TME can be transformed from pro-tumor phenotypes to anti-tumor phenotypes by IFN-β, IFN-γ, and retinoic acid. Reverse action can be achieved through TNF-α, tumor growth factor-β (TGF-β), IL-6, G-CSF, and IL-35, whereas IL-17 has a dual effect, in which subtle concentration changes influence the dynamic shift of neutrophils. ADCC, antibody-dependent cell-mediated cytotoxicity; Arg-1, arginase 1; CCL3, C-C motif chemokine ligand 3; CXCL9, C-X-C motif chemokine ligand 9; Mac-1, macrophage-1 Ag; MDSCs, myeloid-derived suppressor cells; MMP-9, matrix metalloproteinase 9; MPO, myeloperoxidase; NE, neutrophil elastase; NO, nitric oxide; ROS, reactive oxygen species; TANs, tumor-associated neutrophils; TNF-α, tumor necrosis factor-α; TGF-β, tumor growth factor-β; VEGF-α, vascular endothelial growth factor-α.
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Cancer Biology & Medicine
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