Leveling Up the Controversial Role of Neutrophils in Cancer: When the Complexity Becomes Entangled

Abstract

Neutrophils are the most abundant immune cell in the circulation of human and act as gatekeepers to discard foreign elements that have entered the body. They are essential in initiating immune responses for eliminating invaders, such as microorganisms and alien particles, as well as to act as immune surveyors of cancer cells, especially during the initial stages of carcinogenesis and for eliminating single metastatic cells in the circulation and in the premetastatic organs. Since neutrophils can secrete a whole range of factors stored in their many granules as well as produce reactive oxygen and nitrogen species upon stimulation, neutrophils may directly or indirectly affect carcinogenesis in both the positive and negative directions. An intricate crosstalk between tumor cells, neutrophils, other immune cells and stromal cells in the microenvironment modulates neutrophil function resulting in both anti- and pro-tumor activities. Both the anti-tumor and pro-tumor activities require chemoattraction towards the tumor cells, neutrophil activation and ROS production. Divergence is seen in other neutrophil properties, including differential secretory repertoire and membrane receptor display. Many of the direct effects of neutrophils on tumor growth and metastases are dependent on tight neutrophil–tumor cell interactions. Among them, the neutrophil Mac-1 interaction with tumor ICAM-1 and the neutrophil L-selectin interaction with tumor-cell sialomucins were found to be involved in the neutrophil-mediated capturing of circulating tumor cells resulting in increased metastatic seeding. On the other hand, the anti-tumor function of neutrophils was found to rely on the interaction between tumor-surface-expressed receptor for advanced glycation end products (RAGE) and Cathepsin G expressed on the neutrophil surface. Intriguingly, these two molecules are also involved in the promotion of tumor growth and metastases. RAGE is upregulated during early inflammation-induced carcinogenesis and was found to be important for sustaining tumor growth and homing at metastatic sites. Cathepsin G was found to be essential for neutrophil-supported lung colonization of cancer cells. These data level up the complexity of the dual role of neutrophils in cancer.

Intratumoral pro-oxidants promote cancer immunotherapy by recruiting and reprogramming neutrophils to eliminate tumors

“…The outcome of these changes is to promote a more immunosuppressive environment, supporting the ongoing growth and development of tumors. In fact, inflammation-induced ROS at low levels can, by itself, also be a tumor growth and metastasis stimulant [ 45 , 146 ].…”

“…These findings allow for a better understanding of the situation and influence that the TAN subtypes can have on the anticancer versus pro-tumor protective aspects (reviewed in [19,20,43]). Several more recent reports have compared differences between these TAN subtypes, facilitating their identification and highlighting their importance to cancer [2,[44][45][46][47]. Their distinct properties can be summarized in that the N1 subtype are pro-inflammatory, express CXCL10 (a.k.a.…”

Tumor microenvironment-related multigene prognostic prediction model for breast cancer

“…Notably, C4 and C5 breast cancer had high neutrophil infiltration, while C6 breast cancer had lower levels of neutrophil infiltration. As one of the most important immune cell types, neutrophils play a vital role in cancer progression, such as by directly eliminating cancer cells, releasing factors that affect the tumor microenvironment (TME), and producing reactive oxygen and nitrogen species [ 39 ]. These anti-tumor effects might account for the better prognosis of C4 and C5 breast cancer.…”

Neutrophil dynamics and inflammaging in acute ischemic stroke: A transcriptomic review

“…N1 neutrophils have hyper-segmented nuclei that are seen in mature neutrophils while N2 neutrophils have banded or ring-shaped nuclei exhibited in immature neutrophils ( Eruslanov et al, 2017 ). N1 neutrophils secrete inflammatory molecules, such as cytokines and effector molecules, including IL-1β, IL-12, TNFα, IFNγ, NO, CXCL13, CCL3, CC6, CXCL10, and hydrogen peroxide ( Andzinski et al, 2016 ; Sionov, 2021 ). N1 neutrophils are also characterized by the surface expression of Ly6G, CD11b, CD54, and CD86 ( Wang et al, 2018 ; Li et al, 2019 ; Figure 3 ).…”