Abstract
Natural killer (NK) cells are a population of innate lymphoid cells playing a pivotal role in host immune responses against infection and tumor growth. These cells have a powerful cytotoxic activity orchestrated by an intricate network of inhibitory and activating signals. The importance of NK cells in controlling tumor growth and in mediating a robust anti-metastatic effect has been demonstrated in different experimental mouse cancer models. Consistently, high density of tumor-infiltrating NK cells has been linked with a good prognosis in multiple human solid tumors. However, there are also tumors that appear to be refractory to NK cell-mediated killing for the presence of an immunosuppressive microenvironment affecting NK cell function. Immunotherapeutic strategies aimed at restoring and increasing the cytotoxic activity of NK cells in solid tumors, including the adoptive transfer of NK and CAR-NK cells, are currently employed in preclinical and clinical studies. In this review, we outline recent advances supporting the direct role of NK cells in controlling expansion of solid tumors and their prognostic value in human cancers. We summarize the mechanisms adopted by cancer cells and the tumor microenvironment to affect NK cell function, and finally we evaluate current strategies to augment the antitumor function of NK cells for the treatment of solid tumors.
Highlights
Natural killer (NK) cells are a specialized population of innate lymphoid cells (ILCs) that mediates cytotoxic functions against damaged, infected, and pre-malignant cells through an intricate network of signals that allow for rapid activation [1]
NK cell cytotoxicity is mainly regulated by the secretion of effector molecules (IFN-γ, TNF-α, NO, IL-2, IL-12, IL-15, IL-18, and IL-21), and the interplay between inhibitory and activating signals originating at the cell surface from NK cell-inhibitory receptors (NK-IRs) and NK cell-activating receptors (NK-ARs), respectively
In this Review, we discuss recent evidence for a direct role of NK cells in controlling tumor expansions and summarize the mechanisms adopted by tumor cells and the tumor microenvironment (TME) to affect NK cell functions in solid tumors
Summary
Natural killer (NK) cells are a specialized population of innate lymphoid cells (ILCs) that mediates cytotoxic functions against damaged, infected, and pre-malignant cells through an intricate network of signals that allow for rapid activation [1]. NK cell cytotoxicity is mainly regulated by the secretion of effector molecules (IFN-γ, TNF-α, NO, IL-2, IL-12, IL-15, IL-18, and IL-21), and the interplay between inhibitory and activating signals originating at the cell surface from NK cell-inhibitory receptors (NK-IRs) and NK cell-activating receptors (NK-ARs), respectively. NK-IRs promote the effector function upon interaction with ligands expressed on normal and healthy cells. The downregulation of inhibitory ligands and the expression of ligands for NK-ARs on cancer cells can trigger NK cells to kill them and secrete cytokines, such as IFN-γ and TNF-α. Blocking interaction between NK-IRs and their ligands or enhancing NK-ARs–ligand binding may represent a promising strategy to generate an antitumor activity
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