Tumor-Associated Neutrophils: New Targets for Cancer Therapy

Abstract

Studies have begun to emerge showing critical roles for neutrophils in tumorigenesis. Neutrophils can have a significant impact on the tumor microenvironment via their production of cytokines and chemokines, which influence inflammatory cell recruitment and activation. Additionally, products secreted from neutrophils, such as reactive oxygen species and proteinases, have defined and specific roles in regulating tumor cell proliferation, angiogenesis, and metastasis. Although evidence suggests that neutrophils act in a decidedly protumor capacity in vivo, recent studies indicate that neutrophils may be manipulated to exhibit cytotoxicity against tumors. Herein, we explore the idea of targeting tumor-associated neutrophils as a means of antitumor therapy and the important ramifications such manipulation could pose to host tissues. Cancer Res; 71(7); 2411-6. Ó2011 AACR.

Proinflammatory Proteins S100A8/S100A9 Activate NK Cells via Interaction with RAGE

“…Neutrophils constitute the majority of infiltrating cells in acute inflammatory tissues and work as phagocytes and in pathogen killing (23). In addition, numerous other functions are currently attributed to neutrophils, such as the capacity to regulate various aspects of the inflammatory, immune, angiogenic, hematopoietic, wound-healing, antiviral, and antitumoral responses (24,25). Recent evidence indicated that there is crosstalk between neutrophils and NK cells as follows: NK cellderived IFN-g modulates the survival, migration into inflammatory sites, and functional responses of neutrophils, and conversely, neutrophil-derived IL-15 and IL-18 are essential for NK cell activation and proliferation (4).…”

Angiotensin converting enzyme inhibitors and angiotensin II receptor antagonist attenuate tumor growth via polarization of neutrophils toward an antitumor phenotype

“…16,17 Hypersegmented neutrophils showed increased cytotoxicity against tumor cells, 16 and attenuated tumor growth. 16,33 However, little is known regarding the induction mechanism of this neutrophil phenotype. In the current study, we found the role of Ang II on the polarization of neutrophils into antitumoral phenotype.…”

The Multifaceted Roles Neutrophils Play in the Tumor Microenvironment

“…Significant controversy surrounds the function of neutrophils in the context of cancer. Neutrophils are often recruited to the tumor microenvironment where they have been shown to either promote or inhibit tumor growth [6][7][8][9][10][11]. There are several lines of evidence suggesting that neutrophils may exert direct cytotoxic activities towards the tumor, or indirectly lead to tumor regression through recruitment and induction of tumor-specific T cell responses [12][13][14][15][16][17][18].…”

“…Tumor-associated neutrophils ("TANs"), like macrophages, may acquire an anti-tumorigenic "N1" or protumorigenic "N2" phenotype and are classified according to their activation state, cytokine repertoire and effects on tumor growth [7,[9][10][11]60]. The N1 cells are characterized by cytotoxic activity towards tumor cells and an immunostimulatory profile (i.e., TNFα high , CCL3 high , ICAM-1 high , Arginase low ), whereas N2 neutrophils are characterized by upregulation of the chemokines CCL2, 3,4,8,12, and 17, and CXCL1, 2, 8 and 16 [10].…”

“…Neutrophil Mobilization in Cancer Human cancers often induce elevated numbers of circulating neutrophils [6,7,[9][10][11]. The consequences of cancer-induced neutrophilia in human patients will be further discussed in the section discussing "Prognostic Values of Neutrophils and Other Myeloid Subtypes in Cancer Patients".…”