Journal
IMMUNOBIOLOGY
Volume 219, Issue 7, Pages 547-553Publisher
ELSEVIER GMBH
DOI: 10.1016/j.imbio.2014.03.007
Keywords
Interleukin-15; Gene transfer; Natural killer cells; Natural killer cell line
Categories
Funding
- National Natural Science Foundation of China [30671901]
- Ministry of Science and Technology of the People's Republic of China [2012AA020901, 2012ZX10002-014, 2007AA021109, 2007AA021010]
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Genetic modification of NK cells may provide new possibilities for developing effective cancer immunotherapy by improving NK cell function and specificity. We previously established human interleukin-15 (hIL-15) gene-modified NKL cells (NKL-IL15) and demonstrated their therapeutic efficiency against human hepatocellular carcinoma (HCC) in vitro. To further assess the applicability of NKL-IL15 cells in adoptive cellular immunotherapy, we further investigated their natural cytotoxicity against HCC in vivo in the present study. NKL-IL15 cells exhibited strong inhibition on the growth of transplanted human HCC tumors in xenograft nude mouse models. Further investigation showed that NKL-IL15 cells expressed much higher levels of cytolysis-related molecules, including NKp80, TRAIL, granzyme B, IFN-gamma, and TNF-alpha, than parental NKL cells in response to HCC stimulation. Moreover, soluble mediators secreted by NKL-IL15 cells decreased HCC cell proliferation; in particular, NKL-IL15-derived TNF-alpha and IFN-gamma induced higher NKG2D ligand expression on target cells and resulted in the increased susceptibility of HCCs to NKL-mediated cytolysis. These results show that hIL-15 gene-modified human NK cells can augment the anti-tumor effect of NK cells on human HCC in vivo and suggest their promising applicability as a new candidate for adoptive immunotherapy against HCCs in the future. (C) 2014 Elsevier GmbH. All rights reserved.
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