Ex vivo expansion of highly cytotoxic human NK cells by cocultivation with irradiated tumor cells for adoptive immunotherapy

Seon Ah Lim, Tae Jin Kim, Jung Eun Lee, Chung Hee Sonn, Kwanghee Kim, Jiyoung Kim, Jong Gwon Choi, Il Kyu Choi, Chae Ok Yun, Jae-Hong Kim, Cassian Yee, Vinay Kumar, Kyung-Mi Lee

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28 Citations (Scopus)

Abstract

Adoptive natural killer (NK) cell therapy may offer an effective treatment regimen for cancer patients whose disease is refractory to conventional therapy. NKcells can kill a wide range of tumor cells by patterned recognition of target ligands. We hypothesized that tumor targets sensitive to NK lysis would drive vigorous expansion of NK cells from human peripheral blood mononuclear cells (PBMC). Here, we provide the basis for developing a novel ex vivo expansion process. By screening class I-negative or -mismatched tumor cell lines we identified a Jurkat Tlymphoblast subline termed KL-1, which was highly effective in specifically expanding NK cells. KL-1 addition to PBMC cultures achieved approximately 100-fold expansion of NK cells with nearly 90% purity, accompanied by reciprocal inhibition of T-cell growth. Marked elevations in expression of activation receptors, natural cytotoxicity receptors (NKp30, NKp44), and adhesion molecules (CD11a, ICAM-1) were associated with high tumor-lytic capacity, in both in vitro and in vivo models. KL-1-mediated expansion of NK cells was contact dependent and required interactions with CD16, the Fcg receptor on NK cells, with ligands that are expressed on B cells. Indeed, B-cell depletion during culture abrogated selective NK cell expansion, while addition of EBV-transformed B cells further augmented NK expansion to approximately 740-fold. Together, our studies define a novel method for efficient activation of human NK cells that employs KL-1-lysed tumor cells and cocultured B cells, which drive a robust expansion of potent antitumor effector cells that will be useful for clinical evaluation.

Original languageEnglish
Pages (from-to)2598-2607
Number of pages10
JournalCancer Research
Volume73
Issue number8
DOIs
Publication statusPublished - 2013 Apr 15

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

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    Lim, S. A., Kim, T. J., Lee, J. E., Sonn, C. H., Kim, K., Kim, J., Choi, J. G., Choi, I. K., Yun, C. O., Kim, J-H., Yee, C., Kumar, V., & Lee, K-M. (2013). Ex vivo expansion of highly cytotoxic human NK cells by cocultivation with irradiated tumor cells for adoptive immunotherapy. Cancer Research, 73(8), 2598-2607. https://doi.org/10.1158/0008-5472.CAN-12-2893