Abstract
Neutrophils have been extensively described in the pathophysiology of autoimmune and infectious diseases. Accumulating evidence also suggests the important role of neutrophils in cancer progression through their interaction with cancer and immune cells in blood and in the tumor microenvironment (TME). Most studies have described neutrophils as key drivers of cancer progression, due to their involvement in various tumor promoting functions including proliferation, aggressiveness, and dissemination, as well as in immune suppression. However, such studies were focusing on late-stages of tumorigenesis, in which chronic inflammation had already developed. The role of tumor-associated neutrophils (TANs) at early stages of tumor development remains poorly described, though recent findings indicate that early-stage TANs may display anti-tumor properties. Beyond their role at tumor site, evidence supported by NLR retrospective studies and functional analyses suggest that blood neutrophils could also actively contribute to tumorigenesis. Hence, it appears that the phenotype and functions of neutrophils vary greatly during tumor progression, highlighting their heterogeneity. The origin of pro- or anti-tumor neutrophils is generally believed to arise following a change in cell state, from resting to activated. Moreover, the fate of neutrophils may also involve distinct differentiation programs yielding various subsets of pro or anti-tumor neutrophils. In this review, we will discuss the current knowledge on neutrophils heterogeneity across different tissues and their impact on tumorigenesis, as well as neutrophil-based therapeutic strategies that have shown promising results in pre-clinical studies, paving the way for the design of neutrophil-based next generation immunotherapy.
Highlights
Pacôme Lecot 1, Matthieu Sarabi 1, Manuela Pereira Abrantes 1, Julie Mussard 1, Leo Koenderman 2, Christophe Caux 1, Nathalie Bendriss-Vermare 1 and Marie-Cécile Michallet 1*
Current immunotherapies mostly rely on the adaptive immune system, involving adaptive immune checkpoints such as CTLA-4, PD-1, and PD-L1
Inhibition of the innate immune checkpoints Tyro3, Axl, and Mertk tyrosine kinase receptors, mostly expressed by tumorassociated macrophages (TAMs), displayed additional therapeutic effects when combined to the anti-PD-1 monoclonal antibody in a murine model of triple-negative breast cancer [206]
Summary
Aside from the molecular signals driving cancer, several studies have demonstrated the contribution of the host-driven inflammatory response to tumor progression and/or to treatment outcome [1,2,3,4]. Neutrophils are key players in the inflammatory response. They are released into the bloodstream after maturation and differentiation from the bone marrow reservoir [5]. The production of neutrophils has been estimated to range from 1 to 2 × 1011 cells per day at steady state in a healthy adult. Neutrophils represent 50–70% of all circulating leucocytes in humans, while they account for 10–25% in mice [6]
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