Abstract
Despite advances in the diagnostic and therapeutic modalities, the prognosis of several solid tumor malignancies remains poor. Different factors associated with solid tumors including a varied genetic signature, complex molecular signaling pathways, defective cross talk between the tumor cells and immune cells, hypoxic and immunosuppressive effects of tumor microenvironment result in a treatment resistant and metastatic phenotype. Over the past several years, immunotherapy has emerged as an attractive therapeutic option against multiple malignancies. The unique ability of natural killer (NK) cells to target cancer cells without antigen specificity makes them an ideal candidate for use against solid tumors. However, the outcomes of adoptive NK cell infusions into patients with solid tumors have been disappointing. Extensive studies have been done to investigate different strategies to improve the NK cell function, trafficking and tumor targeting. Use of cytokines and cytokine analogs has been well described and utilized to enhance the proliferation, stimulation and persistence of NK cells. Other techniques like blocking the human leukocyte antigen-killer cell receptors (KIR) interactions with anti-KIR monoclonal antibodies, preventing CD16 receptor shedding, increasing the expression of activating NK cell receptors like NKG2D, and use of immunocytokines and immune checkpoint inhibitors can enhance NK cell mediated cytotoxicity. Using genetically modified NK cells with chimeric antigen receptors and bispecific and trispecific NK cell engagers, NK cells can be effectively redirected to the tumor cells improving their cytotoxic potential. In this review, we have described these strategies and highlighted the need to further optimize these strategies to improve the clinical outcome of NK cell based immunotherapy against solid tumors.
Highlights
Natural Killer (NK) cells are the effector cells that constitute a key part of the innate immune system
Some approaches aiming at decreasing circulating transforming growth factor beta (TGF-β), blocking ligand-receptor interactions or inhibiting TGF-β signaling pathways to enhance natural killer (NK) based therapies are currently under investigation pre-clinically and clinically including TGF-β neutralizing antibody, TGF-β receptor I kinase inhibitors, SMAD3-Silenced NK Cells, NK cells engineered with a dominant negative receptor II for TGF-β, NK cells engineered to express a chimeric receptor with TGFβ type II receptor extracellular and transmembrane domains and the intracellular domain of NK cell-activating receptor NKG2D (Table 6)
NK cell based applications are a promising alternative for immunotherapy of solid tumors
Summary
Natural Killer (NK) cells are the effector cells that constitute a key part of the innate immune system. The success stories have been less exciting against solid tumors, due to lack of appropriate immunologic targets, that are highly expressed on surface of tumor tissue with relative absence on the non-vital tissues to avoid “on-target/off-tumor” effects [13] These genetically modified effector cells have to overcome the challenges posed by the physical barriers preventing infiltration into the tumor tissues and hostile tumor microenvironment [14, 15]. Unlike CAR T cells, NK cell based therapies have the advantage of overcoming the limitation posed by the antigen escape mechanism to a certain extent due to their inherent ability to recognize and kill tumor cells without prior sensitization. To overcome the limitation of small number of active NK cells in peripheral blood, our group and others have successfully expanded active NK cells in vitro by short term culture with cytokines alone, using cytokines and co-culture
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