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

Abstract

Notwithstanding the well-recognized involvement of chronic neutrophilic inflammation in the initiation phase of many types of epithelial cancers, a growing body of evidence has also implicated these cells in the pathogenesis of the later phases of cancer development, specifically progression and spread. In this setting, established tumors have a propensity to induce myelopoiesis and to recruit neutrophils to the tumor microenvironment (TME), where these cells undergo reprogramming and transitioning to myeloid-derived suppressor cells (MDSCs) with a pro-tumorigenic phenotype. In the TME, these MDSCs, via the production of a broad range of mediators, not only attenuate the anti-tumor activity of tumor-infiltrating lymphocytes, but also exclude these cells from the TME. Realization of the pro-tumorigenic activities of MDSCs of neutrophilic origin has resulted in the development of a range of adjunctive strategies targeting the recruitment of these cells and/or the harmful activities of their mediators of immunosuppression. Most of these are in the pre-clinical or very early clinical stages of evaluation. Notable exceptions, however, are several pharmacologic, allosteric inhibitors of neutrophil/MDSC CXCR1/2 receptors. These agents have entered late-stage clinical assessment as adjuncts to either chemotherapy or inhibitory immune checkpoint-targeted therapy in patients with various types of advanced malignancy. The current review updates the origins and identities of MDSCs of neutrophilic origin and their spectrum of immunosuppressive mediators, as well as current and pipeline MDSC-targeted strategies as potential adjuncts to cancer therapies. These sections are preceded by a consideration of the carcinogenic potential of neutrophils.

Prognostic Significance of the Neutrophil/Lymphocyte Ratio in Patients undergoing Treatment with Nivolumab for Recurrent Non-Small-Cell Lung Cancer

“…Recruitment of neutrophils to the TME is achieved via production of the myeloid growth factor, G-CSF by tumors. Granulocyte colony-stimulating factor-mediated accelerated neutrophil production in the bone marrow, together with release of tumor-derived, neutrophil-attracting chemokines, particularly CXCL5 and CXCL8, promotes influx of neutrophils into the TME [ 37 , 39 ]. On entering the TME, tumor-associated neutrophils encounter a cytokine environment that favors the transition of these cells to a highly immunosuppressive, protumorigenic phenotype.…”

“…On entering the TME, tumor-associated neutrophils encounter a cytokine environment that favors the transition of these cells to a highly immunosuppressive, protumorigenic phenotype. These reprogrammed neutrophils are known variously as T-lymphocyte-suppressive neutrophils, polymorphonuclear leukocyte-myeloid-derived suppressor cells or type N2 protumorigenic neutrophils [ 37 , 39 ]. The most prominent cytokine involved in promoting the transition of these cells to a protumorigenic phenotype is TGFβ1 derived from various types of immune cells that populate the TME, including MDSCs per se , regulatory T cells (Tregs) and M2-like macrophages.…”

“…Even in the case of those who are least likely to respond well to immune checkpoint-targeted therapy based on an NLR value of ≥5, early identification may qualify such patients for adjunctive neutrophil-targeted therapies, many of which are in the early stages of clinical evaluation [ 37 , 39 , 42 ] but again this contention is subject to stringent validation.…”

COVID-19–Induced Modifications in the Tumor Microenvironment: Do They Affect Cancer Reawakening and Metastatic Relapse?

“…Among cells of the innate immune system, neutrophils play a prominent role in fighting microbial infections but also in inflicting tissue damage. Furthermore, neutrophils are involved in a network of inflammatory reactions that promote all the stages of tumor initiation, progression, angiogenesis and metastasis (61,62). Neutrophils generate reactive oxygen and nitrogen species, release proteases, arginase, ectonucleotidases, matrix metalloproteinases, prostaglandin E2, cyclooxygenases, IL-10 and TGFb1 (62) and express Fas-ligand and PD-L1, which induce lymphocyte apoptosis and immune suppression (63,64).…”

Cynanchum paniculatumand Its Major Active Constituents for Inflammatory-Related Diseases: A Review of Traditional Use, Multiple Pathway Modulations, and Clinical Applications

“…Chronic inflammation plays a major role in various chronic diseases, such as respiratory, cardiovascular, gastrointestinal, hepatobiliary, urogenital, neurological, skeletal, rheumatological systems, and cancer diseases [43][44][45][46][47][48]. e effect of Cynanchum paniculatum and its derivatives on [31,[49][50][51][52].…”