Abstract
Metastasis represents the leading cause of cancer-related death mainly owing to the limited efficacy of current anticancer therapies on advanced malignancies. Although immunotherapy is rendering promising results in the treatment of cancer, many adverse events and factors hampering therapeutic efficacy, especially in solid tumors and metastases, still need to be solved. Moreover, immunotherapeutic strategies have mainly focused on modulating the activity of T cells, while Natural Killer (NK) cells have only recently been taken into consideration. NK cells represent an attractive target for cancer immunotherapy owing to their innate capacity to eliminate malignant tumors in a non-Major Histocompatibility Complex (MHC) and non-tumor antigen-restricted manner. In this review, we analyze the mechanisms and efficacy of NK cells in the control of metastasis and we detail the immunosubversive strategies developed by metastatic cells to evade NK cell-mediated immunosurveillance. We also share current and cutting-edge clinical approaches aimed at unleashing the full anti-metastatic potential of NK cells, including the adoptive transfer of NK cells, boosting of NK cell activity, redirecting NK cell activity against metastatic cells and the release of evasion mechanisms dampening NK cell immunosurveillance.
Highlights
Natural Killer (NK) cells are cytotoxic immune cells with an innate capacity for eliminating transformed cells in a non-major histocompatibility complex (MHC) and non-tumor antigen-restricted manner [1]
Tumor-infiltrating lymphocytes were observed in less-differentiated tumors with mesenchymal characteristics. These suggest that the epithelial-to-mesenchymal transition (EMT) process may constitute a cancer immune checkpoint and that colorectal tumor cells must develop mechanisms to escape from Natural killer group 2D (NKG2D)-mediated immune responses in order to progress through the metastatic process [45,46]
NK cells can be pre-activated with IL-12, IL-15 and IL-18. This approach has been used to generate the so-called Cytokine-induced memory-like (CIML) NK cells with potent in vitro and in vivo anti-leukemia responses along with improved clinical responses in patients with Acute Myeloid Leukemia (AML) in the context of a first-in-human phase I clinical trial [110]
Summary
Natural Killer (NK) cells are cytotoxic immune cells with an innate capacity for eliminating transformed cells in a non-major histocompatibility complex (MHC) and non-tumor antigen-restricted manner [1]. Natural killer group 2D (NKG2D) is a relevant activating receptor, which recognizes a group of stress-inducible molecules termed MHC class I polypeptide-related sequence A and B (MICA and MICB) and UL16 binding protein molecules (ULBP1-6), which are restrictedly expressed on stressed and transformed cells [6,7]. By this complex pattern of receptors, NK cells may kill a broad range of cancer cells. NK cells regulate the innate and adaptive immune response through the secretion of cytokines with potent antitumor activity, such as interferon-gamma (IFN-γ)
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