Neutrophil dynamics in the tumor microenvironment

Abstract

The tumor microenvironment profoundly influences the behavior of recruited leukocytes and tissue resident immune cells. These immune cells, which inherently have environmentally-driven plasticity necessary for their roles in tissue homeostasis, dynamically interact with tumor cells and the tumor stroma and play critical roles in determining the course of disease. Among these immune cells, neutrophils were once considered much more static within the tumor microenvironment; however, some of these earlier assumptions were the product of the notorious difficulty in manipulating neutrophils in vitro. Technological advances that allow us to study neutrophils in context are now revealing the true roles of neutrophils in the tumor microenvironment. Here we discuss recent data generated by some of these tools and how it might be synthesized into more elegant ways of targeting these powerful and abundant effector immune cells in the clinic.5 58, 61-63, 67, 68), providing opportunities for therapeutic intervention. Indeed, CXCR2 inhibitors are being trialed in cancer patients (NCT04477343, NCT03161431, NCT03177187, PRIMUS003).Although the molecules regulating neutrophil expansion and recruitment to tumors are shared across the entire population, neutrophils can exhibit striking functional differences, and information on their diversity continues to emerge. The mechanisms by which neutrophils are polarized towards pro-or antitumor states primarily occurs through cytokines, such as TGFb, IFNb, IFNg, G-CSF and GM-CSF (10-13, 26, 50, 69). Tumor hypoxia is another important regulator of neutrophil phenotype and polarization, since counteracting hypoxia in an autochthonous mouse model of PTEN-driven uterine cancer decreases neutrophil-mediated cancer progression (70). The importance of neutrophil polarization and diversity in cancer has been recently reviewed elsewhere (1-3, 71, 72). However, it is important to mention that specific nomenclature describing neutrophil polarization states have led to confusion when comparing data in the field. These terms include N1/N2 neutrophils, which were coined to mirror T helper cell (Th)-1/2 immunity and M1/M2 macrophages; granulocytic or polymorphonuclear myeloid-derived suppressor cells (G/PMN-MDSCs), which are T cell-inhibiting neutrophils; as well as low-density neutrophils (LDNs) and high-density neutrophils (HDNs), whose name stems from the location of neutrophils in density gradients. There are many biological arguments for and against the continued use of these terms (1, 2, 73, 74), but overall, we argue that to more accurately describe emerging data in the field they should be avoided. The terms above are either too narrow or too simplistic in their ability to capture the inherent plasticity of neutrophils, or they perpetuate the incorrect notion that N1, N2, MDSCs, LDNs, HDNs are cell populations distinct from neutrophils. These terms describe pathological activation or maturation states of neutrophils, rather than separate cell types (75). Neutrophil participation in metastasisT...

Radiotherapy combined with immunotherapy: the dawn of cancer treatment

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Post treatment NLR is a predictor of response to immune checkpoint inhibitor therapy in patients with esophageal squamous cell carcinoma

“…Unfortunately, PLR, MLR and SII were not associated with the response to the anti-PD-1 treatment in ESCC patients, as a result of which, it was assuming that NLR was a vital factor reflecting the system inflammation response after anti-PD-1 therapy. Neutrophil and lymphocyte were important components of tumor immune microenvironment and played a role in tumor-associated immunity [ 36 – 38 ], but the mechanism of the significance of peripheral blood NLR which representing systemic inflammation in tumor-associated immunity was still unclear. In our study, we also evaluated the NLR level of the tumor free population and found that the NLR level of ESCC patients had a significantly higher trend than that of the tumor free population.…”

Neutrophil and Natural Killer Cell Interactions in Cancers: Dangerous Liaisons Instructing Immunosuppression and Angiogenesis

“…Several studies support the pro-tumoral properties of N2 neutrophils, that predominantly express CC and CXC chemokines such as CCL2, 3, 4, 8, 12, and 17 and CXCL1, 2, 8, and 16, in addition to higher expression of vascular endothelial growth factor (VEGF), CXCR4 and matrix metalloproteinase 9 (MMP9) [14][15][16] (Figure 1B). Molecularly, one of the first mechanisms through which neutrophils promote tumor growth is represented by the release of ROS, which in turn induce DNA damage, which are essential for cancer initiation, cell proliferation, and increasing the mutational load [14][15][16].…”