MULT1E/mIL-12: a novel bifunctional protein for natural killer cell activation.

Abstract

Natural killer (NK) cells have the potential to be effective killers of tumor cells. They are governed by inhibitory and activating receptors like NKG2D, whose ligands are normally upregulated in cells that are stressed, like cancer cells. Advanced cancer cells, however, have ways to reduce these ligands' expression, leaving them less detectable by NK cells. Along with these receptors, NK cells also require activating cytokines, like interleukin 12 (IL-12). The goal of this study is to develop a novel bi-functional fusion protein for enhanced NK cell activation. The proposed protein combines the extracellular domain of the NKG2D ligand Mouse UL-16-binding protein-like transcript 1 (MULT1E) and mouse IL-12 (mIL-12). It is hypothesized that when expressed by tumor cells, the protein will activate NK and other killer cells using the NKG2D receptor, and deliver mIL-12 to the NK cells where it can interact with the IL-12R and enhance cytotoxicity. The fusion protein, when expressed by engineered tumor cells, indeed activated NK cells in vitro as assayed by increased production of interferon-γ and cytotoxicity and significantly reduced tumor growth in vivo. Although the study is preliminary, the data suggest that the MULT1E/mIL-12 bi-functional fusion protein is an effective activator of NK cells for cancer treatment.

• Authors: A Tietje, J Li, X Yu, Y Wei
• Journal: Gene therapy (Gene Ther) Vol. 21 Issue 5 Pg. 468-75 (May 2014) ISSN: 1476-5462 [Electronic] England
• PMID: 24572784 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Carrier Proteins
• Histocompatibility Antigens Class I
• Klrk1 protein, mouse
• Membrane Proteins
• NK Cell Lectin-Like Receptor Subfamily K
• Receptors, Interleukin-12
• Recombinant Fusion Proteins
• UL16 binding protein 1, mouse
• Interleukin-12
• Interferon-gamma

Topics

• Animals
• Carrier Proteins (genetics, immunology, pharmacology)
• Cell Line, Tumor
• Cell Proliferation
• Cell- and Tissue-Based Therapy
• Cytotoxicity, Immunologic (immunology)
• Female
• Histocompatibility Antigens Class I (genetics, immunology, pharmacology)
• Interferon-gamma (biosynthesis)
• Interleukin-12 (genetics, immunology, pharmacology)
• Killer Cells, Natural (drug effects, immunology)
• Lung Neoplasms (immunology, prevention & control)
• Lymphocyte Activation
• Membrane Proteins
• Mice
• Mice, Inbred C57BL
• Monitoring, Immunologic
• NK Cell Lectin-Like Receptor Subfamily K (biosynthesis)
• Receptors, Interleukin-12 (immunology)
• Recombinant Fusion Proteins (genetics, immunology, pharmacology)