Neutrophils: Orchestrators of the Malignant Phenotype

Abstract

Neutrophils are the first leukocytes recruited to sites of inflammation, where they execute anti-microbial functions to eliminate infectious agents. These functions include phagocytosis, release of reactive oxygen species and the formation of neutrophil extracellular traps via NETosis. Neutrophils are receiving increasing attention in the context of cancer, where these same neutrophil-associated functions are also important for modulating tumor growth and metastatic progression. Neutrophils are phenotypically heterogeneous and, depending on the context, exert anti- or pro-tumorigenic functions. Increasing evidence also suggests an important role of neutrophils and their involvement in promoting multiple steps of the metastatic cascade. The steps include: (1) local invasion and intravasation of cancer cells into circulation, (2) survival of cancer cells in the bloodstream and extravasation at a distant site, (3) early cancer cell seeding/survival, and (4) progressive growth of cancer cells to form macroscopic metastases. Although neutrophil functions designed to eliminate infectious agents can also eliminate tumor cells, their dysregulation can promote tumor growth and enable metastasis at multiple steps along the metastatic cascade. In this review, we will provide an overview of the current advances in neutrophil biology in the context of cancer. We also discuss the emerging field of immunometabolism, in which the rewiring of alternative metabolic pathways within neutrophils can impact their pro-tumorigenic/pro-metastatic functions.

Keywords: NETosis; immunometabolism; immunosuppression; metabolic plasticity/flexibility; metastasis; neutrophils; tumor growth.

Figure 1

Neutrophil functions that promote tumor growth and metastasis. To support primary tumor growth, neutrophils can mediate T cell suppression and alter macrophage differentiation. Neutrophil release of TIMP-1 enhances tumor cell invasion by inducing epithelial-to-mesenchymal transition. Once in circulation, circulating tumor cells interact with neutrophils, which enables tumor cell proliferation. Secretion of various pro-inflammatory markers such as IL-8, IL-1β, or MMPs can mediate increased tumor cell extravasation. In addition, neutrophils can inhibit intraluminal NK-mediated killing of circulating cancer cells, leading to increased extravasation. At the metastatic site, various systemic, and microenvironmental factors can promote neutrophil infiltration. Neutrophils can awaken dormant cancer cells by promoting ECM remodeling and angiogenesis. Lastly, continued growth of the metastatic lesion is facilitated by key neutrophil-dependent mechanisms, which include angiogenesis, proliferation, immune suppression, and immune exclusion. CSF-1, colony stimulating factor 1; TIMP1, tissue inhibitor of matrix metalloprotease; PD-L1, programmed death ligand 1; TGFβ, transforming growth factor β; ROS, reactive oxygen species; MMP, matrix metalloproteinases; GM-CSF, granulocyte macrophage colony stimulating factor; ANGPTL2, angiopoetin like-2; FGF2, fibroblast growth factor 2; LTB₄, leukotriene B₄; iNOS, inducible nitric oxide synthase; NET, neutrophil extracellular trap; CAF, cancer-associated fibroblast.

Figure 2

Metabolic changes in cancer-associated neutrophils. Neutrophils, which possess few mitochondria, are reliant on glycolysis to generate ATP to fuel effector functions such as phagocytosis, generation of reactive oxygen species, and NETosis. In cancer, neutrophils upregulate oxidative phosphorylation (OXPHOS) and fatty acid transporters to mediate many neutrophil functions; including migration and T cell suppression. Under nutrient limiting conditions, such as low glucose, neutrophils can reprogram their metabolism to break down fatty acids or utilize certain amino acids (glutamate, proline) to fuel pro-tumorigenic/pro-metastatic functions. PPP, pentose phosphate pathway; GLUT, glucose transporter; MCT, Monocarboxylate transporter 1; TCA, tricarboxylic acid cycle; FATP2, fatty acid transport protein 2; AA, arachidonic acid; PGE₂, prostaglandin E2.