Autonomous Growth and Increased Cytotoxicity of Natural Killer Cells Expressing Membrane-Bound interleukin-15

Blood. 2014 Aug 14;124(7):1081-8. doi: 10.1182/blood-2014-02-556837. Epub 2014 Jul 8.

Abstract

Natural killer (NK) cell survival and, hence, cytotoxicity requires cytokine support. We determined whether expression of interleukin-15 (IL-15) in a nonsecretory, membrane-bound form could sustain NK cell growth. We linked the human IL15 gene to that encoding CD8α transmembrane domain (mbIL15). After retroviral transduction, human NK cells expressed mbIL15 on the cell surface; IL-15 secretion was negligible. Survival of mbIL15-NK cells without interleukin-2 (IL-2) after 7-day culture was vastly superior to that of mock-transduced NK cells (P < .001, n = 15) and of NK cells expressing nonmembrane-bound IL-15 (P = .025, n = 9); viable mbIL15-NK cells were detectable for up to 2 months. In immunodeficient mice, mbIL15-NK cells expanded without IL-2 and were detectable in all tissues examined (except brain) in much higher numbers than mock-transduced NK cells (P < .001). Expansion further increased with IL-2. The primary mechanism of mbIL15 stimulation was autocrine; it activated IL-15 signaling and antiapoptotic signaling. NK cells expressing mbIL15 had higher cytotoxicity against leukemia, lymphoma, and solid tumor cells in vitro and against leukemia and sarcoma cells in xenograft models. Thus, mbIL15 confers independent growth to NK cells and enhances their antitumor capacity. Infusion of mbIL15-NK cells would allow NK cell therapy without the potential adverse effects of cytokine administration.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • CD8 Antigens / genetics
  • CD8 Antigens / immunology
  • CD8 Antigens / metabolism
  • Cell Line
  • Cell Line, Tumor
  • Cell Membrane / immunology
  • Cell Membrane / metabolism
  • Cell Proliferation*
  • Cell Survival / drug effects
  • Cell Survival / immunology
  • Cytotoxicity, Immunologic / immunology*
  • Humans
  • Immunotherapy, Adoptive / methods
  • Interleukin Receptor Common gamma Subunit / genetics
  • Interleukin-15 / genetics
  • Interleukin-15 / immunology*
  • Interleukin-15 / metabolism
  • Interleukin-2 / immunology
  • Interleukin-2 / pharmacology
  • K562 Cells
  • Killer Cells, Natural / immunology*
  • Killer Cells, Natural / metabolism
  • Mice, Inbred NOD
  • Mice, Knockout
  • Mice, SCID
  • U937 Cells
  • Xenograft Model Antitumor Assays

Substances

  • CD8 Antigens
  • CD8 antigen, alpha chain
  • Il2rg protein, mouse
  • Interleukin Receptor Common gamma Subunit
  • Interleukin-15
  • Interleukin-2