A Rosetta Stone for Breast Cancer: Prognostic Value and Dynamic Regulation of Neutrophil in Tumor Microenvironment

Abstract

Increasing evidence has revealed that the initiation and progression of breast cancer are greatly affected by the immune environment. Neutrophils are the most abundant leucocytes in circulation and act as the spearhead in inflammation, including in breast cancer. Circulating neutrophils are closely related to the prognosis of breast cancer patients, and tumor-infiltrating neutrophils have varied functions at different stages of breast cancer, such as antitumor or tumor-promoting neutrophils, which are termed N1 and N2 neutrophils, respectively. In this review, we will discuss the utility of circulating neutrophils for predicting prognosis and therapeutic efficacy and the underlying mechanisms of their chemotaxis, the dynamic regulation of their antitumor or protumor functions and their different spatial distributions in tumor microenvironment. Finally, we also discuss the possibility of targeting neutrophils as a therapeutic strategy in breast cancer.

Prognostic Relevance of Neutrophil to Lymphocyte Ratio (NLR) in Luminal Breast Cancer: A Retrospective Analysis in the Neoadjuvant Setting

“…While a different function of TILs across the different breast cancer subtypes has been demonstrated, as described above, very little is known about the role and activation of neutrophils. Neutrophils are emerging as major players in defining the fate of cancer development, promoting tumor growth and progression towards a metastatic disease or favoring killing of tumor cells and cancer regression [ 60 ]. The first scenario has been highlighted by a meta-analysis of the association between tumor-associated neutrophils (TANs) and prognosis in different cancer types [ 61 ].…”

“…The former is mainly determined by exposure of neutrophils to type-I interferon [ 65 ]; the latter is prompted by transforming growth factor (TGF)-β [ 64 , 66 , 67 ] and granulocyte colony-stimulating factor (G-CSF) [ 68 ]. N1 neutrophils exert an anti-tumor effect through the production of hypochlorous acid (HOCl), reactive oxygen species (ROS), tumor necrosis factor (TNF)-α, and nitric oxide (NO) and promote an immunogenic microenvironment by inhibiting interleukin (IL)-17 production and exhibiting increased antibody-dependent cell cytotoxicity (ADCC) [ 60 ]. To the contrary, N2 neutrophils support tumor growth through the production of vascular endothelial growth factor (VEGF), IL-1β, IL-6, and IL-17, promote an immune-suppressive microenvironment by recruiting Treg, and favor the metastatic process by inducing neutrophil extracellular trap (NET) formation [ 60 ], a type of neutrophil death leading to the release of DNA–histone complexes and proteins to form net-like structures.…”

The immunomodulatory effects of endocrine therapy in breast cancer

“…S100A-8, S100A-9, CXCL-1, and CXCL-2), tissue-remodeling enzymes (MMP-3 and MMP-9) and COX-2 during mammary involution [ 31 ]. Protumoral neutrophils exacerbate the formation of tumor-promoting microenvironment, which further encourages BC progression [ 31 , 32 ].…”

A Score for Predicting Freedom from Progression of Children and Adolescents with Hodgkin Lymphoma

“…Moreover, neutrophils are involved in the immune response, as an important part of the tumor microenvironment, which plays a central role in cHL pathogenesis [11][12][13]. Neutrophil counts and neutrophil/lymphocyte ratio (NLR) have been proposed as prognostic factors in several solid and hematological tumors, including adults with cHL [14][15][16][17][18][19][20]. A recent study demonstrated that NLR could predict clinical outcomes in PET-negative adult patients with cHL [21].…”