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.

前列腺癌患者的自然杀伤 (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相关。对于晚期前列腺癌患者来说，当标准治疗方案已用尽时，免疫疗法是一种有前途的方法。随着基于 NK 细胞的疗法的迅速出现，了解触发 NK 细胞杀死已形成免疫逃避策略的癌细胞的机制非常重要。在考虑调节 NK 细胞激活的方法时，改变晚期前列腺癌细胞的细胞因子谱可能是一个值得探索的领域。我们之前已经证明，将细胞因子 IL-27 与 TLR3 激动剂 Poly(I:C) 相结合，可以改变晚期前列腺癌模型中的细胞因子分泌，PC3 和 DU145 细胞。在此，我们扩展了之前的工作，研究原代人类 NK 细胞对前列腺癌细胞死亡的影响。体外共培养模型。用 IL-27 和 Poly(I:C) 刺激 PC3 和 DU145 细胞会诱导 IFN-β 分泌，这是激活原代人类 NK 细胞杀死这些受刺激的前列腺癌细胞所必需的。与 DU145 细胞相比，PC3 细胞对 NK 细胞介导的杀伤更加敏感，这是由于 IL-27 和 Poly(I:C) 刺激产生的 IFN-β 水平存在差异。IFN-β 增加了共培养 NK 细胞的颗粒酶 B 分泌和膜结合 TRAIL 表达。我们进一步证明这些 NK 细胞以部分 TRAIL 依赖性方式杀死 PC3 细胞。这项工作为如何改善 NK 细胞的细胞毒功能以靶向癌细胞提供了机制见解。