Neutrophil Heterogeneity in Cancer: From Biology to Therapies

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.

Role of the Neutrophil in the Pathogenesis of Advanced Cancer and Impaired Responsiveness to Therapy

“…In this setting, accelerated myelopoiesis appears to result from the production of bone marrow-stimulating growth factors by tumor cells, most notably the cytokines granulocyte colony-stimulating factor (G-CSF) and granulocyte/macrophage colony-stimulating factor (GM-CSF) [30][31][32][33][34][35]. In this context, it is noteworthy that an increased circulating neutrophil/lymphocyte ratio (NLR, defined as the absolute circulating neutrophil count divided by the lymphocyte count) is widely regarded as being a negative prognostic indicator in many, but not all, types of cancer reviewed in [36]. Other lines of evidence have strongly implicated neutrophilic infiltration of tumors as being predictive of adverse outcomes [36,37].…”

“…In this context, it is noteworthy that an increased circulating neutrophil/lymphocyte ratio (NLR, defined as the absolute circulating neutrophil count divided by the lymphocyte count) is widely regarded as being a negative prognostic indicator in many, but not all, types of cancer reviewed in [36]. Other lines of evidence have strongly implicated neutrophilic infiltration of tumors as being predictive of adverse outcomes [36,37].…”

Circulating neutrophil subsets in advanced lung cancer patients exhibit unique immune signature and relate to prognosis

“…The traditional concept that neutrophils are terminally differentiated cells, whose function is limited to antimicrobial protection, is being gradually revised. Neutrophils have been shown to impact tumor biology in multiple ways, affecting tumor growth and the metastatic process . Several studies have provided compelling evidence for neutrophils' protumorigenic role, while others have advocated for neutrophils antitumor and antimetastatic potential .…”

“…In this context, the role of neutrophils in lung cancer has recently sparked increased interest, as evidence for neutrophils' significant and diverse role in cancer biology accumulates. [1][2][3] The traditional concept that neutrophils are terminally differentiated cells, whose function is limited to antimicrobial protection, is being gradually revised. Neutrophils have been shown to impact tumor biology in multiple ways, affecting tumor growth and the metastatic process.…”

“…Neutrophils have been shown to impact tumor biology in multiple ways, affecting tumor growth and the metastatic process. [3][4][5] Several studies have provided compelling evidence for neutrophils' protumorigenic role, 6,7 while others have advocated for neutrophils antitumor and antimetastatic potential. 8,9 It is now generally accepted that neutrophils can acquire both pro-or antitumor function as part of an immunosuppressive switch occurring in cancer.…”