Abstract
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. Cancer Immunol Res; 6(8); 965-77. ©2018 AACR.
Highlights
Cancer is still one of the leading causes of death in the world
Real-time PCR and ELISA revealed that TGFb1-mediated suppression on the production of anticancer effectors (i.e., IFNg, granzyme B, and perforin) as well as the expression of activation markers (NKp30 and NKp44) were attenuated in Natural killer (NK)-92-S3KD cells compared with NK-92-EV cells (Fig. 2; Supplementary Fig. S5)
These results demonstrated that knockdown of SMAD3 in the human NK-92 cells attenuated TGFb1-mediated immunosuppression, which in turn enhanced these cells' cancer-killing effect and cytotoxic effector production
Summary
Cancer is still one of the leading causes of death in the world. Chemotherapy, and radiotherapy have been the mainstays of cancer treatment for decades. Outcomes are still unsatisfactory due to side effects, drug resistance, recurrence, and metastasis. Versatile, and adaptable, leading to primary and secondary resistance [1]. Side effects induced by systemic administration of cytotoxic anticancer drugs can produce serious clinical problems [2]. Therapies that target the tumor microenvironment show promise as cancer, tumor growth, invasion, and metastasis rely on stromal conditions [3]
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