Drug name: Natural killer cells


Related CSCTT Targets

CD133high CSCs [ref.1]

Introduction

Natural killer (NK) cells are a subset of innate immune cells with specified functions in host defense[1]. Typically, immune cells detect major histocompatibility complex (MHC) presented on infected cell surfaces, triggering cytokine release, causing lysis or apoptosis. NK cells are unique, however, as they have the ability to recognize stressed cells in the absence of antibodies and MHC, allowing for a much faster immune reaction. They were named "natural killers" because of the initial notion that they do not require activation to kill cells that are missing "self" markers of MHC class 1[2].

NK cells are defined as large granular lymphocytes (LGL) and constitute the third kind of cells differentiated from the common lymphoid progenitor-generating B and T lymphocytes[3]. NK cells differ from natural killer T cells (NKTs) phenotypically, by origin and by respective effector functions; often, NKT cell activity promotes NK cell activity by secreting IFNγ. In contrast to NKT cells, NK cells do not express T-cell antigen receptors (TCR) or pan T marker CD3 or surface immunoglobulins (Ig) B cell receptors, but they usually express the surface markers CD16 (FcγRIII) and CD56 in humans.

The NK cell activity are sustained and adjust by activating and inhibitory NK cell receptors. NK cell receptors can be differentiated based on function. NK cell activation is determined by the balance of inhibitory and activating receptor stimulation. For example, if the inhibitory receptor signaling is more prominent, then NK cell activity will be inhibited; similarly, if the activating signal is dominant, then NK cell activation will results[4].

Some examples:
Activating receptors include Ly49, NCR (natural cytotoxicity receptors), CD94, CD16 et al.
Inhibitory receptors include Killer-cell immunoglobulin-like receptors (KIRs), ILT or LIR (leukocyte inhibitory receptors) et al.
NK cell receptors[2]
NK cells are considered as cytotoxic cells during antiviral, antimicrobial and antiparasitic responses. And NK cells are also cytotoxic to transformed cells and tumor cells via direct killing or induction of apoptosis[1].

Since NK cells recognize target cells when they express nonself HLA antigens, autologous NK cell infusions have not shown any antitumor effects. It play critical roles in host immunity against cancer. Current NK cell-based cancer immunotherapy aims to overcome NK cell paralysis using several approaches. One approach uses expanded allogeneic NK cells, which are not inhibited by self histocompatibility antigens like autologous NK cells, for adoptive cellular immunotherapy. Another adoptive transfer approach uses stable allogeneic NK cell lines, which is more practical for quality control and large-scale production. A third approach is genetic modification of fresh NK cells or NK cell lines to highly express cytokines, Fc receptors and/or chimeric tumor-antigen receptors. Therapeutic NK cells can be derived from various sources, including peripheral or cord blood cells, stem cells or even induced pluripotent stem cells (iPSCs), and a variety of stimulators can be used for large-scale production in laboratories or good manufacturing practice (GMP) facilities, including soluble growth factors, immobilized molecules or antibodies, and other cellular activators[5].

[1] Yin, T., et al. (2016). "Human cancer cells with stem cell-like phenotype exhibit enhanced sensitivity to the cytotoxicity of IL-2 and IL-15 activated natural killer cells." Cell Immunol 300: 41-45.
[2] Vivier, E., et al. (2011). "Innate or adaptive immunity? The example of natural killer cells." Science 331(6013): 44-49.
[3] Male, D. (2012). "Immunology (8th ed.)."
[4] Terunuma, H., et al. (2008). "Potential role of NK cells in the induction of immune responses: implications for NK cell-based immunotherapy for cancers and viral infections." Int Rev Immunol 27(3): 93-110.
[5] Cheng, M., et al. (2013). "NK cell-based immunotherapy for malignant diseases." Cell Mol Immunol 10(3): 230-252.

Schema

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Reference

  • [1] Cytokine-induced killer (CIK) cells bound with anti-CD3/anti-CD133 bispecific antibodies target CD133(high) cancer stem cells in vitro and in vivo.
    Huang, J., et al. (2013). Clin Immunol 149(1): 156-168. [ 23994769 ]

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