IFN-β activates cytotoxic function of human natural killer cells toward IL-27 and poly(I:C) stimulated PC3 and DU145 cells

IF 3.7 4区 医学 Q2 CELL BIOLOGY
Olena Kourko, Lindsey G. Hawke, Mark L. Ormiston, Katrina Gee
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Abstract

Natural killer (NK) cell phenotype and function are altered in patients with prostate cancer, and increased NK cell activity is associated with a better prognosis in patients with disease. For patients with advanced stage prostate cancer, immunotherapies are a promising approach when standard treatment options have been exhausted. With the rapid emergence of NK cell-based therapies, it is important to understand the mechanisms by which NK cells can be triggered to kill cancer cells that have developed immune-evasive strategies. Altering the cytokine profiles of advanced prostate cancer cells may be an area to explore when considering ways in which NK cell activation can be modulated. We have previously demonstrated that combining the cytokine, IL-27, with TLR3 agonist, poly(I:C), changes cytokine secretion in the advanced prostate cancer models, PC3 and DU145 cells. Herein, we extend our previous work to study the effect of primary human NK cells on prostate cancer cell death in an in vitro co-culture model. Stimulating PC3 and DU145 cells with IL-27 and poly(I:C) induced IFN-β secretion, which was required for activation of primary human NK cells to kill these stimulated prostate cancer cells. PC3 cells were more sensitized to NK cell-mediated killing when compared to DU145 cells, which was attributed to differential levels of IFN-β produced in response to stimulation with IL-27 and poly(I:C). IFN-β increased granzyme B secretion and membrane-bound TRAIL expression by co-cultured NK cells. We further demonstrated that these NK cells killed PC3 cells in a partially TRAIL-dependent manner. This work provides mechanistic insight into how the cytotoxic function of NK cells can be improved to target cancer cells.

IFN-β激活人自然杀伤细胞对IL-27和poly(I:C)刺激的PC3和DU145细胞的细胞毒功能
前列腺癌症患者的自然杀伤(NK)细胞表型和功能发生改变,NK细胞活性的增加与疾病患者更好的预后有关。对于晚期前列腺癌症患者,当标准治疗方案已经用尽时,免疫疗法是一种很有前途的方法。随着基于NK细胞的疗法的迅速出现,重要的是要了解NK细胞被触发杀死癌症细胞的机制,这些细胞已经发展出免疫逃避策略。在考虑调节NK细胞活化的方法时,改变晚期前列腺癌症细胞的细胞因子谱可能是一个需要探索的领域。我们之前已经证明,将细胞因子IL-27与TLR3激动剂poly(I:C)结合,可以改变晚期前列腺癌症模型PC3和DU145细胞中的细胞因子分泌。在此,我们扩展了我们之前的工作,在体外共培养模型中研究原代人NK细胞对前列腺癌症细胞死亡的影响。用IL-27和poly(I:C)刺激PC3和DU145细胞诱导IFN-β分泌,这是激活原代人NK细胞以杀死这些刺激的前列腺癌症细胞所必需的。与DU145细胞相比,PC3细胞对NK细胞介导的杀伤更敏感,这归因于IL-27和poly(I:C)刺激产生的IFN-β水平不同。IFN-β通过共培养的NK细胞增加颗粒酶B的分泌和膜结合TRAIL的表达。我们进一步证明,这些NK细胞以部分TRAIL依赖的方式杀死PC3细胞。这项工作为如何改善NK细胞的细胞毒性功能以靶向癌症细胞提供了机制上的见解。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
Cellular immunology
Cellular immunology 生物-免疫学
CiteScore
8.20
自引率
2.30%
发文量
102
审稿时长
30 days
期刊介绍: Cellular Immunology publishes original investigations concerned with the immunological activities of cells in experimental or clinical situations. The scope of the journal encompasses the broad area of in vitro and in vivo studies of cellular immune responses. Purely clinical descriptive studies are not considered. Research Areas include: • Antigen receptor sites • Autoimmunity • Delayed-type hypersensitivity or cellular immunity • Immunologic deficiency states and their reconstitution • Immunologic surveillance and tumor immunity • Immunomodulation • Immunotherapy • Lymphokines and cytokines • Nonantibody immunity • Parasite immunology • Resistance to intracellular microbial and viral infection • Thymus and lymphocyte immunobiology • Transplantation immunology • Tumor immunity.
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