Abstract
Lung cancer remains the leading cause of cancer mortality in the United States, with non-small cell lung cancer (NSCLC) accounting for around 85% of cases. Of particular concern is the poor responsiveness of this malignancy to therapy, resulting in a very low 5-year survival rate (17.4%) and a prominent tendency to progress to metastatic disease. A number of very recent studies, both pre-clinical and clinical, have implicated the neutrophil in both the pathogenesis and unsatisfactory response to therapy of NSCLC. In this context, movement of neutrophils into the tumor microenvironment (TME) is a common feature of NSCLC. Indeed neutrophils are the dominant type of immune cell in the NSCLC TME, creating a highly immunosuppressive milieu that is not only conducive to tumor growth and spread, but also represents a significant obstacle to the success of anti-tumor therapy, especially novel immunotherapies. The clinically relevant adverse impact of a neutrophil predominance both systemically and in the TME of patients with NSCLC is underscored by the negative prognostic value of both a persistent neutrophilia and, in particular, a high (≥5) neutrophil:lymphocyte ratio. On a more positive note, however, recognition of the involvement of the neutrophil in both the pathophysiology of NSCLC and treatment failure has enabled identification of neutrophil-targeted strategies that have the potential to serve as adjuncts to standard anti-cancer therapies, including immunotherapy. These strategies together with a consideration of the immunosuppressive, pro-tumorigenic properties of the neutrophil represent the major thrusts of this review.
Highlights
Lung cancer is usually diagnosed at a late stage and remains the leading cause of death from cancer among men and women, accounting for approximately 25% of the 9.6 million total cancer deaths recorded globally in 2018 with an overall five-year survival rate of 5% in the case of advanced, metastatic disease (Didowska et al, 2016)
Validated biomarkers identified to date that are predictive of responsiveness to immunotherapy in nonsmall cell lung cancer (NSCLC) include the tumor mutational burden (TMB) and expression of programmed cell death ligand (PD-L1) (Pharaon et al, 2020)
Non-small cell lung cancer appears to be adept at recruiting neutrophils to the tumor microenvironment (TME) and reprogramming these cells under the influence of various factors such as granulocyte-macrophage colony stimulating factor (GM-CSF), TGF-β1, IL1β and IL-17A to acquire an immunosuppressive phenotype known as myeloidderived suppressor cells (MDSCs) of granulocytic origin and N2-type neutrophils
Summary
Lung cancer is usually diagnosed at a late stage and remains the leading cause of death from cancer among men and women, accounting for approximately 25% of the 9.6 million total cancer deaths recorded globally in 2018 with an overall five-year survival rate of 5% in the case of advanced, metastatic disease (Didowska et al, 2016). This approach resulted in the identification of 22 different types of tumor-associated leukocytes in the TMEs, the presence of which was correlated with overall survival (OS) (Gentles et al, 2015) In this context, the authors identified significant, inverse prognostic associations between gene expression profiles typical of polymorphonuclear leukocytes (neutrophils) that were evident “across the cancer landscape”, most prominently with the lung adenocarcinoma variant of NSCLC, as well as with breast cancer, subtypes of the latter malignancy were not mentioned (Gentles et al, 2015). Currently available evidence linking tumor progression and treatment failure to recruitment of neutrophils to the TME of patients with NSCLC, is somewhat limited, necessitating additional stringently controlled studies, in the clinical setting, to enable firm conclusions This contention is supported by the findings of another recent study that reported somewhat different findings to those mentioned above (Tamminga et al, 2020). These findings are consistent with the co-existence of augmentative suppressive interactions between different types of suppressor cells in the TME of NSCLC (Wang et al, 2018; Ferreira et al, 2020)
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