Neutrophil and Natural Killer Cell Interactions in Cancers: Dangerous Liaisons Instructing Immunosuppression and Angiogenesis

Abstract

The tumor immune microenvironment (TIME) has largely been reported to cooperate on tumor onset and progression, as a consequence of the phenotype/functional plasticity and adaptation capabilities of tumor-infiltrating and tumor-associated immune cells. Immune cells within the tumor micro (tissue-local) and macro (peripheral blood) environment closely interact by cell-to-cell contact and/or via soluble factors, also generating a tumor-permissive soil. These dangerous liaisons have been investigated for pillars of tumor immunology, such as tumor associated macrophages and T cell subsets. Here, we reviewed and discussed the contribution of selected innate immunity effector cells, namely neutrophils and natural killer cells, as "soloists" or by their "dangerous liaisons", in favoring tumor progression by dissecting the cellular and molecular mechanisms involved.

Keywords: immunosuppression; natural killer cells; neutrophil-NK cell crosstalk; neutrophils; tumor angiogenesis; tumor microenvironment.

Figure 1

Neutrophil and NK cell subsets. Human neutrophils (A) are characterized by CD11b, CD66b, CD14, and CD16 expression. Mimicking the M1 or M2-like macrophage polarization, neutrophils in the tumor microenvironment are also characterized by the capability to acquire two opposite phenotypes. N1 neutrophils (B) show anti-tumoral activities and are characterized by the expression of chemokine (C-C motif) ligand 3 (CCL3), tumor necrosis factor α (TNFα), arginase, and intercellular adhesion molecule 1 (ICAM1); in contrast, N2 neutrophils (C) work as tumor-promoters and express CC and CXC chemokines (CCL2, 3, 4, 8, 12 and 17 and CXCL1, 2, 8, and 16), vascular endothelial growth factor (VEGF), matrix metalloprotease 9 (MMP9), and CXCR4 receptor. Human NK cell subsets (D) are characterized by CD56 expression. Cytolytic NK cells express CD56 and CD16 (CD56^dimCD16⁺) and can release perforin and granzyme; cytokine producer NK cells lose CD16 expression and increase CD56 expression (CD56^brigthCD16⁻⁾ with the production of cytokines including TNFα and interferon γ (IFNγ); the last subset is named decidual cells (dNKs) that displayed higher expression of CD56 with CD9 and CD49a markers (CD56^superbrigthCD16⁻CD9⁺CD49a⁺) and support angiogenesis through the release of VEGF, placental growth factor (PlGF), and interleukin 6 (IL6). A similar subset named decidual-like NK cells is also found in the tumor microenvironment (TME).

Figure 2

Neutrophil–NK cell crosstalk in tumor microenvironment. Neutrophils can (A) induce reduction in CCR1 expression on NK cells, impairing the NK cells’ infiltration capability. Interference with PDL1-PD1 (B) interactions in the TME, resulting in reduced NK cell capability to release IFNγ. Neutrophils can also modulate the expression of activating receptor NKp46 on NK cells through (C) the release of different molecules that include: (i) neutrophil-derived Cathepsin G (CG) reduces NKp46 on NK cells; similar; (ii) reactive oxygen species (ROS) can downmodulate NKp46 on cytotoxic CD56^dimCD16⁺NK cells while they can upregulate this receptor on cytokine-producer CD56^brigthCD16⁻ NK cells; (iii) elastase and lactoferrin release exert a wide effect increasing cytotoxicity and reducing angiogenesis. NK-derived IFNγ, a key mediator in TME, can be inversely modulated by ARG1 and IL12 from neutrophils (D). (i) Indeed, neutrophil-derived ARG1 can abrogate IFNγ released from NK, improving NK pro-angiogenic features; (ii) while neutrophil-derived IL12 through STAT4 activation increases IFNγ and perforin production by NK cells. NK cell–neutrophil crosstalk (E) can be modulated by NK-derived IFNγ, which acts by decreasing pro-angiogenic features of tumor associated neutrophils (TANs). Indeed, NK cells or IFNγ depletion increase TANs’ pro-angiogenic features.

Figure 3

Neutrophil–NK cell crosstalk in angiogenesis modulation. The bidirectional crosstalk between neutrophils and NK cells can negatively modulate angiogenesis thus (A) neutrophil derived IL12, 15, and 18 stimulate IP10, perforin, and granzyme production in NK cells that block FGF2 effect. In TME, NK cells can improve angiogenesis (B) through the production of IFNγ and granulocyte-macrophages colony-stimulating factor (GM-CSF), which results in neutrophil expression of CD11b, CD62L, and CD64 surface antigens and release or VEGF and MMP9, in a STAT3 and c-Myc dependent manner. Moreover, in neutrophils, CD64 expression is linked to increasing production of ARG1. On the other hand, (C) NK-derived IFNγ prevents VEGF release from neutrophils, reducing angiogenesis stimulation. Finally, panels B and C show how IFNγ, produced by NK cells, act as a double edge sword by exerting both pro-angiogenic and anti-angiogenic activities.