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

Maria Teresa Palano,Daniela Gallo,Antonino Bruno,Barbara Bassani,Martina Cucchiara,Matteo Gallazzi,Lorenzo Mortara,Andrea De Lerma Barbaro

doi:10.3390/vaccines9121488

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.

Highlights

In a transplantable tumor mouse model obtained with subcutaneous injection of melanoma and fibrosarcoma cells, Jablonska and colleagues have shown that CD11b+ neutrophils are responsible for angiogenesis stimulation since expressed high levels of genes encoding for vascular endothelial growth factor (VEGF) and matrix metalloproteinase 9 (MMP9), together with transcription factor c-myc and STAT3, which are positive regulators of both VEGF and MMP9 [79] (Figure 3B)
ARG1 [56] could play a positive role for angiogenesis and, in addition, STAT3 could increase pro-angiogenic VEGF and MMP9 production [79] (Figure 3B), CD64-expressing neutrophils can contribute to angiogenic switch in MM
It is clear that the immune cell phenotype/functional switch and the dangerous liaisons occurring between different immune cells in the tumor micro- and macro-environments, represent crucial events impacting cancer progression and the success of the therapeutic regimens

Summary

Brief Overview on Neutrophils and Cancers

Neutrophils are the most abundant circulating leukocytes, accounting for 50–70% of blood cells. It has been shown that even if neutrophil activation induces damage to the surrounding tissues, through the radical oxygen species (ROS) release, proteolytic enzymes, and antimicrobial proteins, they are crucial for tissue regeneration, being able to phagocyte debris, to produce growth factors and pro-angiogenic proteins that promote re-vascularization, and to induce macrophage recruitment, which in turn supports and accelerates tissue repair [9] These opposite functions, already described for other myeloid cells, such as macrophages, suggests the existence of opposing polarization states (pro-tumoral or anti-tumoral) of neutrophils in cancer [10,11,12]. Neutrophils can exert direct anti-tumor or pro-tumoral functions, the regulatory role of these cells in orchestrating other cells of the tumor microenvironment (TME) of both myeloid and lymphoid origin has clearly been stated [24]

Brief Overview on NK Cells and Cancers

Neutrophil–NK Cell Interactions

Conclusions