Neutrophils in advanced non-small cell lung cancer
View/ Open
Grecian2020_Redacted.pdf (15.43Mb)
Grecian2020.pdf (23.01Mb)
Date
30/11/2020Item status
Restricted AccessEmbargo end date
30/11/2021Author
Grecian, Robert John
Metadata
Abstract
Lung cancer is the third most common cancer in the UK; 87% are histologically nonsmall cell lung cancer (NSCLC). At the time of diagnosis, patients frequently have
advanced disease, with poor one-year survival due to metastatic burden. The
immune system should act as a key line of defence; recognising, killing and clearing
malignant cells. However, ineffective immune responses contribute to cancer
progression. Neutrophils are active players in the metastatic environment, but there
is limited data regarding human neutrophil populations in advanced lung cancer.
Greater understanding of the interplay between extrinsic cell signals and intrinsic
cell features in determining neutrophil roles, is also needed.
In this study, to investigate how the extrinsic metastatic NSCLC pleural environment
influences the function of neutrophils, it was modelled in vitro by culturing healthy
donor neutrophils in conditions emulating the pleural space. Tumour necrosis factor
alpha (TNFa) and hypoxia acted as pro-survival signals leading to neutrophil
persistence and NSCLC pleural fluid conditioned neutrophils to suppress CD8+ T
cells through mechanisms including programmed death-ligand 1 (PD-L1)
expression. To establish the phenotype of neutrophil populations in advanced
NSCLC, neutrophils were extracted from the pleural fluid (metastatic site) and blood
of patients. Cellular morphology, surface marker expression and functional assays
were utilised. There was an expanded population of low-density blood neutrophils in
advanced NSCLC, that were not present in health, and a proportion of which were
immature with banded nuclei. Similar immature neutrophils were seen in NSCLC
pleural fluid. NSCLC pleural fluid neutrophils expressed PD-L1 and were long-lived.
To understand how cell-intrinsic features of neutrophil populations in advanced
NSCLC may determine their role in cancer, the populations were defined by their
transcriptomic and proteomic signatures. This provided evidence that implied
NSCLC low-density blood neutrophils represent immature cells that have been
recruited from the bone marrow; they may retain proliferative capacity, have reduced
neutrophil granules, and are pro-survival.
In summary, the data favours a phenotype of sustained neutrophilic inflammation
that is immunosuppressive at the NSCLC metastatic site, with a subpopulation of
immature cells that may be ineffective/ detrimental. This is likely to permit tumour
progression, leading to adverse patient outcomes.