Enhanced Cancer Immunotherapy with Smad3-Silenced NK-92 Cells

• Published in: Cancer immunology research 2018-08, Vol.6 (8), p.965-977
• Main Authors: Wang, Qing-Ming, Tang, Patrick Ming-Kuen, Lian, Guang-Yu, Li, Chunjie, Li, Jinhong, Huang, Xiao-Ru, To, Ka-Fai, Lan, Hui-Yao
• Format: Article
• Language: English
• Subjects: Animals; Cell Line; Extracellular Matrix Proteins - immunology; Gene Silencing; Genetic Engineering - methods; Humans; Immunotherapy - methods; Interferon-gamma - biosynthesis; Killer Cells, Natural - immunology; Liver Neoplasms, Experimental - immunology; Liver Neoplasms, Experimental - therapy; Melanoma, Experimental - immunology; Melanoma, Experimental - therapy; Mice, Inbred NOD; Mice, Knockout; Smad3 Protein - genetics; Smad3 Protein - immunology; Transforming Growth Factor beta - immunology; Tumor Microenvironment - immunology; Xenograft Model Antitumor Assays
• ISSN: 2326-6066; 2326-6074
• DOI: 10.1158/2326-6066.CIR-17-0491

Natural killer (NK) cells, early effectors in anticancer immunity, are paralyzed by TGFβ1, an immunosuppressive cytokine produced by cancer cells. Development and activity of NK cells are largely inhibited in the Smad3-dependent tumor microenvironment. Here, we used genetic engineering to generate a stable SMAD3-silencing human NK cell line, NK-92-S3KD, whose cancer-killing activity and cytokine production were significantly enhanced under TGFβ1-rich condition compared with the parental cell line. Interestingly, we identified that the IFNG gene is a direct E4BP4 target gene. Thus, silencing of SMAD3 allows upregulation of E4BP4 that subsequently promoting interferon-γ (IFNγ) production in the NK-92-S3KD cells. More importantly, NK-92-S3KD immunotherapy increases the production of not only IFNγ, but also granzyme B and perforin in tumors; therefore, inhibiting cancer progression in two xenograft mouse models with human hepatoma (HepG2) and melanoma (A375). Thus, the NK-92-S3KD cell line may be useful for the clinical immunotherapy of cancer. .