The Multifaceted Role of Neutrophils in NSCLC in the Era of Immune Checkpoint Inhibitors

Abstract

Lung cancer is the most common cause of cancer-related death in both males and females in the U.S. and non-small-cell lung cancer (NSCLC) accounts for 85%. Although the use of first- or second-line immune checkpoint inhibitors (ICIs) exhibits remarkable clinical benefits, resistance to ICIs develops over time and dampens the efficacy of ICIs in patients. Tumor-associated neutrophils (TANs) have an important role in modulating the tumor microenvironment (TME) and tumor immune response. The major challenge in the field is to characterize the TANs in NSCLC TME and understand the link between TAN-related immunosuppression with ICI treatment response. In this review, we summarize the current studies of neutrophil interaction with malignant cells, T-cells, and other components in the TME. Ongoing clinical trials are aimed at utilizing reagents that have putative effects on tumor-associated neutrophils, in combination with ICI. Elevated neutrophil populations and neutrophil-associated factors could be potential therapeutic targets to enhance anti-PD1 treatment in NSCLC.

Keywords: immunotherapy; neutrophils; non-small-cell lung cancer; tumor microenvironment.

Figure 1

Functions of pro-tumor neutrophils in the TME. 0TANs secret chemokine, cytokines, and other factors that lead to tumor growth, including ROS, HGF, EGF, PDFF, and PGE₂. TAN-released MMP9, PK2/Bv8, and VEGF also contribute to angiogenesis. TAN can also facilitate metastasis through CXCL2/SNAIL signaling, the formation of NET, and altering lipid metabolism. TANs also contribute to immune suppression through the inhibition of cytotoxic T-cells via PD-L1, ROS, ARG1, and S100a8/A9. They also recruit regulatory T-cells through CCL17 and S100A8/A9. ROS, NO, and ARG1 secreted by TANs can suppress B-cell activity and ROS may lead to the inhibition of NK cell’s anti-tumor activity. Abbreviations: programmed death-ligand 1 (PD-L1), reactive oxygen species (ROS), epidermal growth factor (EGF), hepatocyte growth factor (HGF), arginase 1 (ARG1), S100 calcium-binding protein A8 (S100A8), calprotectin (S100A8/A9), C-C motif chemokine ligand 17 (CCL17), vascular endothelial growth factor (VEGF), metalloproteinase 9 (MMP9), prokineticin 2 (PK2/Bv8), nitric oxide (NO), C-X-C motif chemokine ligand 2 (CXCL2), zinc-finger protein SNAI1 (SNAIL), neutrophil extracellular net (NET), and prostaglandin E2 (PGE₂).

Figure 2

Inhibition of TANs in association with ICI treatment potentially enhances ICI efficacy. Pegfilgrastim targets G-CSF and blocks neutrophil recruitment from the bone marrow. Galuniserib targets TGFβ and potentially inhibits pro-tumor N2 polarization; Reparixin, Navarixin, and BMS-813160 target CXCL1/2/5 chemotaxis of neutrophil; Anlotinib blocks VEGF and PDGF; Marimastat targets MMP 9; and they all aim to inhibit the pro-tumor effect of neutrophils. Sivelestat targets NE; Tocilizumab targets IL-6; Numidargistat targets ARG1; CDDO-Me blocks ROS; and they all aim to reverse the inhibition of cytotoxic T-cells by neutrophils. Tasquinimod targets S100A8/A9 and inhibits the recruitment of regulatory T-cells. Abbreviations: granulocyte colony-stimulating factor (G-CSF), transforming growth factor beta necrosis factor alpha (TGF-β), C-X-C motif chemokine ligand 1/2/5 (CXCL1/2/5), vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF), metalloproteinase 9 (MMP9), neutrophil elastase (NE), interleukin 6 (IL-6), arginase 1 (ARG1), reactive oxygen species (ROS), and S100 calcium-binding protein A8/A9 (S100A8/A9).