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

Abstract

The accumulation of circulating low‐density neutrophils (LDN) has been described in cancer patients and associated with tumor‐supportive properties, as opposed to the high‐density neutrophils (HDN). Here we aimed to evaluate the clinical significance of circulating LDN in lung cancer patients, and further assessed its diagnostic vs prognostic value. Using mass cytometry (CyTOF), we identified major subpopulations within the circulating LDN/HDN subsets and determined phenotypic modulations of these subsets along tumor progression. LDN were highly enriched in the low‐density (LD) fraction of advanced lung cancer patients (median 7.0%; range 0.2%‐80%, n = 64), but not in early stage patients (0.7%; 0.05%‐6%; n = 35), healthy individuals (0.8%; 0%‐3.5%; n = 15), or stable chronic obstructive pulmonary disease (COPD) patients (1.2%; 0.3%‐7.4%, n = 13). Elevated LDN (>10%) remarkably related with poorer prognosis in late stage patients. We identified three main neutrophil subsets which proportions are markedly modified in cancer patients, with CD66b+/CD10low/CXCR4+/PDL1inter subset almost exclusively found in advanced lung cancer patients. We found substantial variability in subsets between patients, and demonstrated that HDN and LDN retain a degree of inherent spontaneous plasticity. Deep phenotypic characterization of cancer‐related circulating neutrophils and their modulation along tumor progression is an important advancement in understanding the role of myeloid cells in lung cancer.

High Throughput Multi-Omics Approaches for Clinical Trial Evaluation and Drug Discovery

“…VDJViewer was specifically developed with the intention to provide single cell data processing for users that do not have advanced bioinformatic expertise, therefore making immunologic single cell data more accessible (69). In addition to modeling antigen markers, scRNA seq, and meta data, this application can also perform pseudo-time analysis and dimensionality reduction (69). As more data and platforms like VDJViewer become available, there is also a need to improve the models that operate within a given platform.…”

Neutrophils: Orchestrators of the Malignant Phenotype

“…Interestingly, LDNs have been identified in patients with breast cancer, lung cancer, head and neck cancers, urologic cancers, and lymphoma ( 7 , 99 – 101 ). In patients with advanced lung cancer, it was reported that higher proportion of LDNs (>10%) predicted poorer survival ( 102 ). These observations are in keeping with the pro-tumorigenic and pro-metastatic functions associated with LDN/N2 neutrophils.…”

<p>A Retrospective Cohort Study on Pretreated Neutrophil-to-Lymphocyte Ratio and Prognosis of Small Cell Lung Cancer: Evidence of Effect Modification by Chemotherapy Regimen</p>

“…Neutrophils can secrete essential factors, including IL-8, VEGF, and elastase for tumor growth and metastases. 21 Shaul et al 29 suggested that the peripheral blood in patients with advanced lung cancer was the preferred site for accumulation of low-density neutrophils that are associated with poor prognosis. Moreover, proinflammatory neutrophils can release neutrophil extracellular traps (NETs) to capture pathogens and function as an antibacterial barrier in the body, although these neutrophils are also associated with the incidence of chronic inflammation and cancer.…”