Abstract
Immune cells, as a consequence of their plasticity, can acquire altered phenotype/functions within the tumor microenvironment (TME). Some of these aberrant functions include attenuation of targeting and killing of tumor cells, tolerogenic/immunosuppressive behavior and acquisition of pro-angiogenic activities. Natural killer (NK) cells are effector lymphocytes involved in tumor immunosurveillance. In solid malignancies, tumor-associated NK cells (TANK cells) in peripheral blood and tumor-infiltrating NK (TINK) cells show altered phenotypes and are characterized by either anergy or reduced cytotoxicity. Here, we aim at discussing how NK cells can support tumor progression and how induction of angiogenesis, due to TME stimuli, can be a relevant part on the NK cell-associated tumor supporting activities. We will review and discuss the contribution of the TME in shaping NK cell response favoring cancer progression. We will focus on TME-derived set of factors such as TGF-β, soluble HLA-G, prostaglandin E2, adenosine, extracellular vesicles, and miRNAs, which can exhibit a dual function. On one hand, these factors can suppress NK cell-mediated activities but, on the other hand, they can induce a pro-angiogenic polarization in NK cells. Also, we will analyze the impact on cancer progression of the interaction of NK cells with several TME-associated cells, including macrophages, neutrophils, mast cells, cancer-associated fibroblasts, and endothelial cells. Then, we will discuss the most relevant therapeutic approaches aimed at potentiating/restoring NK cell activities against tumors. Finally, supported by the literature revision and our new findings on NK cell pro-angiogenic activities, we uphold NK cells to a key host cellular paradigm in controlling tumor progression and angiogenesis; thus, we should bear in mind NK cells like a TME-associated target for anti-tumor therapeutic approaches.
Highlights
Strong evidences suggest that the presence of inflammatory cells within the tumor microenvironment (TME) plays a crucial role in the development and/or progression of tumors [1,2,3]
Tumor cells have developed several mechanisms to evade from Natural killer (NK) cell immunosurveillance, through the modulation of cell surface molecules involved in their recognition and the release of immunosuppressive soluble factors such as TGF-β, HLA-G, prostaglandins and adenosine in the
Several lines of evidence point out the role of NK cells and Mast cells (MCs) in tumor growth and angiogenesis, given their ability to synergize in different pathological conditions [163]
Summary
Strong evidences suggest that the presence of inflammatory cells within the TME plays a crucial role in the development and/or progression of tumors [1,2,3]. A new NK cell subset, termed CD56low CD16low , has been described in the bone marrow (BM) and peripheral blood of pediatric healthy donors and leukemic transplanted patients. This CD56low CD16low NK cell subset is supposed to represent an intermediate stage of differentiation between CD56high CD16+/− and CD56low CD16high [31,32,33]. Elevated number of CD56low CD16low NK cells have been found in the BM on multiple myeloma patients, with decreased expression of activating receptors such as DNAM-1 and NKp30 and impaired cytolytic capabilities [15]
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