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      Autonomous growth and increased cytotoxicity of natural killer cells expressing membrane-bound interleukin-15.

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          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.

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          Author and article information

          Journal
          Blood
          Blood
          1528-0020
          0006-4971
          Aug 14 2014
          : 124
          : 7
          Affiliations
          [1 ] Department of Pediatrics, National University of Singapore, Singapore;
          [2 ] Department of Bone Marrow Transplantation and Cellular Therapy, St. Jude Children's Research Hospital, Memphis, TN; and.
          [3 ] Department of Pediatrics, Niigata University, Niigata, Japan.
          Article
          blood-2014-02-556837
          10.1182/blood-2014-02-556837
          25006133
          da03dfb3-2f48-4eea-b013-e0d96980bfff
          © 2014 by The American Society of Hematology.
          History

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