Abstract
Natural Killer (NK) cells are unique immune cells capable of efficient killing of infected and transformed cells. Indeed, NK cell-based therapies induced response against hematological malignancies in the absence of adverse toxicity in clinical trials. Nevertheless, adoptive NK cell therapies are reported to have exhibited poor outcome against many solid tumors. This can be mainly attributed to limited infiltration of NK cells into solid tumors, downregulation of target antigens on the tumor cells, or suppression by the chemokines and secreted factors present within the tumor microenvironment. Several methods for genetic engineering of NK cells were established and consistently improved over the last decade, leading to the generation of novel NK cell products with enhanced anti-tumor activity and improved tumor homing. New generations of engineered NK cells are developed to better target refractory tumors and/or to overcome inhibitory tumor microenvironment. This review summarizes recent improvements in approaches to NK cell genetic engineering and strategies implemented to enhance NK cell effector functions.
Highlights
Natural killer (NK) cells are part of the innate immune system
Lower NK cell counts and reduced cytotoxicity are associated with higher cancer risks [2, 3], as NK cells kill aberrant somatic cells with downregulated major histocompatibility complex class I (MHC-I) molecules that escape T-cell scrutiny [1]
Blood NK cell counts positively correlate with lower risk for cancer development [2], whereas higher tumor tissue NK cell infiltration correlates with improved treatment outcomes [26, 27]
Summary
Natural killer (NK) cells are part of the innate immune system. Discovered more than 40 years ago, they kill virus-infected cells, counteract tumor formation and initiate innate immune responses [1]. Blood NK cell counts positively correlate with lower risk for cancer development [2], whereas higher tumor tissue NK cell infiltration correlates with improved treatment outcomes [26, 27] This antitumor effect has been comprehensively summarized elsewhere recently [21]. The TME comprises tumor-associated non-malignant cells and extracellular matrix components It secretes suppressive cytokines, like transforming growth factor (TGF)-b [32] and IL-10 [33], or suppressive factors like prostaglandin E2 (PGE2) and adenosine [34, 35] that prevent NK cell mobilization and target tissue infiltration. The trials highlighted a relatively limited effectivity against solid tumors [21] This is caused by low tumor homing and infiltration, short in vivo persistence and impaired NK cell activity in the cancer patients, this by tumor antigen downregulation and the immunosuppressive TME [28]. High transgene expression levels in both primary and ex vivo expanded NK cells [58, 59], can be TABLE 1 | Genetic modification of NK cells with viral methods
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