hIL-15 gene-modified human natural killer cells (NKL-IL15) augments the anti-human hepatocellular carcinoma effect in vivo.
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-γ, and TNF-α, 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-α and IFN-γ 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.
Institute of Immunopharmacology & Immunotherapy, School of Pharmaceutical Sciences, Shandong University, 44 Wenhua West Road, Jinan 250012, PR China.
Wen
W
Jiang
Institute of Immunopharmacology & Immunotherapy, School of Pharmaceutical Sciences, Shandong University, 44 Wenhua West Road, Jinan 250012, PR China.
Cai
C
Zhang
Institute of Immunopharmacology & Immunotherapy, School of Pharmaceutical Sciences, Shandong University, 44 Wenhua West Road, Jinan 250012, PR China.
Zhigang
Z
Tian
Institute of Immunopharmacology & Immunotherapy, School of Pharmaceutical Sciences, Shandong University, 44 Wenhua West Road, Jinan 250012, PR China. Electronic address: zhangj65@sdu.edu.cn.
Jian
J
Zhang
D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000276:immunology* / Q000473:pathology / Q000628:therapy; D002460:Cell Line; D049109:Cell Proliferation; D002470:Cell Survival / Q000276:immunology; D018920:Coculture Techniques; D003602:Cytotoxicity, Immunologic / Q000276:immunology; D005260:Female; D005434:Flow Cytometry; D056945:Hep G2 Cells; D006801:Humans; D016219:Immunotherapy, Adoptive / Q000379:methods; D007371:Interferon-gamma / Q000276:immunology / Q000378:metabolism; D019409:Interleukin-15 / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D007694:Killer Cells, Natural / Q000276:immunology* / Q000378:metabolism / Q000637:transplantation; D008113:Liver Neoplasms / Q000276:immunology* / Q000473:pathology / Q000628:therapy; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D055655:NK Cell Lectin-Like Receptor Subfamily K / Q000276:immunology / Q000378:metabolism; D016019:Survival Analysis; D047368:Tumor Burden / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
D019409:Interleukin-15; C527085:KLRK1 protein, human; D055655:NK Cell Lectin-Like Receptor Subfamily K; D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma
Gene transfer; Interleukin-15; Natural killer cell line; Natural killer cells