Subpopulation Heterogeneity of NK Cells during the Genetic Modification for Subsequent Use in Targeted Therapy.

Obtaining genetically engineered NK cells is a developing area of immunotherapy. In this work, we analyzed the subset heterogeneity of NK cells subjected to retroviral transduction, taking into account the content of adaptive NK cell progenitors. It was shown that subsets KIR2DL2/DL3+, as well as CD57-KIR2DL2/DL3+NKG2C+, can be modified with greater efficiency than the corresponding subsets that do not carry the KIR2DL2/DL3 and NKG2C markers. After genetic modification, the CD57-KIR2DL2/DL3+NKG2C+ cells began to express CD57 de novo, acquiring the adaptive NK cell phenotype.

Current Approaches to Engineering of NK Cells for Cancer Immunotherapy.

Natural Killer (NK) cells belong to a unique subtype of lymphocytes with a great potential for cancer immunotherapy due to their ability to rapidly recognize and efficiently kill tumor cells. Their anti-cancer potential can be further increased by genetic and non-genetic modifications. However, the attempts of genetic improvements of NK cells over the past 20 years have been hampered by the difficulties of gene delivery into this cell type, thus preventing researchers from producing clinically relevant numbers of viable and biologically active NK cells. Currently, several successful approaches to genetic modification of NK cells have been described, and clinically applicable cell therapy products have been characterized. Now that we understand much better the ways of NK cell optimization to enhance their tumor regression-inducing capabilities, novel approaches to engineering NK surface receptors are being developed. In this review, we focus on the advantages and perspectives of various approaches to modification of NK cells. Positive results of several preclinical studies are described, demonstrating that genetically modified NK cells can be comparable to therapeutic T cells in their efficiency of recognizing and destroying tumor targets. Moreover, using allogenic NK cells to treat a number of cancer types might have even wider and eager clinical adoption than cytotoxic T cells due to a much decreased risk of graft versus host reaction inherent in NK cell-based immunotherapeutic products.

Bacterial lipopolysaccharide activates CD57-negative human NK cells.

NK cells play an important regulatory role in sepsis by induction and augmentation of proinflammatory reactions in early stages of the septic process and by suppression of immune response in later stages of inflammation. The present work was aimed at the effect of bacterial lipopolysaccharide (LPS), the main pathogenic factor of sepsis development, on human NK cells ex vivo. We show that LPS activates immature CD57-negative NK cells, which typically constitute less than half of the normal NK cell population in human peripheral blood. Under conditions of NK cell stimulation with IL-2, addition of LPS provokes an increase in IFN-γ production. However, LPS both increased and inhibited NK cell cytotoxic activity. It is important to note that the activation of NK cells on LPS addition was observed in the absence of TLR4 on the NK cell surface. These results confirm our previous data arguing for a direct interaction of LPS with NK cells and evidence an atypical mechanism of LPS-induced NK cell activation without the involvement of surface TLR4.

Inactivated Marburg virus elicits a nonprotective immune response in Rhesus monkeys.

In the present work the kinetics of some indices of immunity (tumor necrosis factor (TNF), interferon (IFN), natural killer cells (NK), lymphocyte proliferation activity, virus-specific antibodies, CD4/CD8 ratio) in response to Marburg virus infection in Macaca mulatta were studied. The different kinetics of immunological parameters for animals which survived Marburg virus infection and for animals which died after infection are shown. A comparison of the indices of IFN, TNF and spontaneous lymphocyte proliferation activity in Macaca mulatta infected with Marburg virus at different stages of life shows the relationship between the increase of these indices and the decrease in the animals' lifespan. Marburg virus immunosuppressive properties were corroborated by studying lymphocyte proliferation activity in response to antigenic stimulation in vitro and the CD4/CD8 index during experimental Marburg virus infection in Macaca mulatta. We conclude that the disease outcome depends on the dynamics of certain immunologic indices such as TNF and IFN.