The Multifaceted Roles Neutrophils Play in the Tumor Microenvironment

Abstract

Neutrophils are myeloid cells that constitute 50-70 % of all white blood cells in the human circulation. Traditionally, neutrophils are viewed as the first line of defense against infections and as a major component of the inflammatory process. In addition, accumulating evidence suggest that neutrophils may also play a key role in multiple aspects of cancer biology. The possible involvement of neutrophils in cancer prevention and promotion was already suggested more than half a century ago, however, despite being the major component of the immune system, their contribution has often been overshadowed by other immune components such as lymphocytes and macrophages. Neutrophils seem to have conflicting functions in cancer and can be classified into anti-tumor (N1) and pro-tumor (N2) sub-populations. The aim of this review is to discuss the varying nature of neutrophil function in the cancer microenvironment with a specific emphasis on the mechanisms that regulate neutrophil mobilization, recruitment and activation.

Priming of neutrophils toward NETosis promotes tumor growth

“…20 In cancer patients, increase in neutrophil count and elevated blood G-CSF have been frequently observed and associated with poor outcome. 2,21 The systemic activation of neutrophils and neutrophilia may also initiate cancer-associated thrombosis as demonstrated in mice. 7 Importantly, our results demonstrate that G-CSF does not have to be locally produced in the tumor to prime neutrophils toward NETosis.…”

“…Indeed, tumors may secrete a wide range of cytokines and chemokines such as TNF-a, interleukin-1, and CXCL2 that attract neutrophils and contribute to intratumoral NETosis. 21,23,24 Moreover, tumors are prothrombotic and the interaction of intratumoral neutrophils with the activated endothelium or platelets via P-selectin would also induce NETosis. 25 Our work and that of others 15 indicates that a closer monitoring of neutrophil counts and activation and a deeper understanding of the tumor environment and the factors that drive NETosis should be of prime importance in the fight against cancer.…”

Plasticity beyond Cancer Cells and the “Immunosuppressive Switch”

“…Specifically, stimulating na€ ve neutrophils with PMA (phorbol 12-myristate 13-acetate) or fMLP (N-Formylmethionyl-leucyl-phenylalanine) when cocultured with tumor cells was sufficient to induce significant cytotoxicity. However, the effect of neutrophil reaches beyond direct cytotoxicity, and neutrophils were also found to play a key role in antibody-dependent cell-mediated cytotoxicity (3). On the other hand, with the evolution of our understanding of the tumor microenvironment, neutrophils were shown to possess a significantly different set of traits.…”

Tumor-associated neutrophils display a distinct N1 profile following TGFβ modulation: A transcriptomics analysis of pro- vs. antitumor TANs

“…[8][9][10] Whereas several studies have provided evidence for neutrophils with pro-tumor functions such as promoting tumor angiogenesis 11 , tumor cell dissemination, and metastatic seeding in distant organs [12][13][14] , others have shown the existence of neutrophils with antitumor and anti-metastatic functions. [15][16][17][18][19][20] These seemingly conflicting reports over the function of neutrophils in cancer is likely due to the existence of multiple neutrophil subsets 21,22 ; a tumor promoting or N2 phenotype and an tumor-inhibitory or N1 phenotype. Interestingly, it has been proposed that there can be phenotypic or functional plasticity, where neutrophils infiltrating a tumor are modulated by cues present in the tumor environment.…”