Abstract
Tumor Associated Neutrophils (TANs) are engaged into the tumor microenvironment by cytokines and chemokines, can be distinguished according to their activation and cytokine status and effects on tumor cell growing in N1 and N2 TANs. N1 TANs exert an antitumor activity, by direct or indirect cytotoxicity. N2 TANs stimulate immunosuppression, tumor growth, angiogenesis and metastasis by DNA instability, or by cytokines and chemokines release. In tumor patients, either a high number of TANs and Neutrophil-to-Lymphocyte Ratio (NLR) do correlate with poor prognosis, and, so far, TAN counts and NLR can be regarded as biomarkers. Owing to the pivotal role of TANs in stimulating tumor progression, therapeutic strategies to target TANs have been suggested, and two major approaches have been proposed: (a) targeting the CXCL-8/CXCR-1/CXCR-2 axis, thereby blocking TANs or (b) targeting substances produced by polymorpho-nuclear cells that promote tumor growth. Many studies have been accomplished either in vitro and in animal models, whereas clinical studies are restrained, presently, due to the risk of inducing immunosuppression. In this review, we deeply discuss the anti-tumorigenic or pro-tumorigenic activity of TANs. In particular, TANs relevance in tumor prognosis and in vitro therapeutic strategies are widely described. On-going clinical trials, aimed to inhibit neutrophil recruitment into the tumor are also accurately debated.
Highlights
Neutrophils represent 50–70% of the myeloid derived white circulating cells in human blood, and are mainly involved in the human innate immunity against invading pathogens [1] Following cytokine stimulation, neutrophils acquire the potentiality to polarize to antitumor (N1) or protumor (N2) phenotype [2,3,4]
Immune profile of N1 Tumor Associated Neutrophils (TANs) is characterized by high levels of an TNFα, CCL3, ICAM-1 and low levels of Arginase axis, whereas N2 neutrophils are characterized by upregulation of the chemokines “CCL2, CCL3, CCL4, CCL8, CCL12, and CCL17, and CXCL1, CXCL2, IL-8/CXCL8 and CXCL16” [4]
We focus on the role played by TANs in pathogenesis and progression of cancer and highlight the potential role of TANs as target for novel cancer therapies
Summary
Neutrophils represent 50–70% of the myeloid derived white circulating cells in human blood, and are mainly involved in the human innate immunity against invading pathogens [1] Following cytokine stimulation, neutrophils acquire the potentiality to polarize to antitumor (N1) or protumor (N2) phenotype [2,3,4]. MMP-9 promotes HCC, lung and pancreatic cancer angiogenesis by promoting neutrophil recruitment [29]. Pro-inflammatory IL-17 promotes neutrophil recruitment in peritumoral HCC tissues, via chemokines production or by activation of IL-17 producing γ δT cells [32].
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