NK cells, lymphocytes of the innate immune system, are important for defense against infectious pathogens and cancer. Classically, the CD56^dim NK cell subset is thought to mediate antitumor responses, whereas the CD56^bright subset is involved in immunomodulation. Here, we challenge this paradigm by demonstrating that brief priming with IL-15 markedly enhanced the antitumor response of CD56^bright NK cells. Priming improved multiple CD56^bright cell functions: degranulation, cytotoxicity, and cytokine production. Primed CD56^bright cells from leukemia patients demonstrated enhanced responses to autologous blasts in vitro, and primed CD56^bright cells controlled leukemia cells in vivo in a murine xenograft model. Primed CD56^bright cells from multiple myeloma (MM) patients displayed superior responses to autologous myeloma targets, and furthermore, CD56^bright NK cells from MM patients primed with the IL-15 receptor agonist ALT-803 in vivo displayed enhanced ex vivo functional responses to MM targets. Effector mechanisms contributing to IL-15–based priming included improved cytotoxic protein expression, target cell conjugation, and LFA-1–, CD2-, and NKG2D-dependent activation of NK cells. Finally, IL-15 robustly stimulated the PI3K/Akt/mTOR and MEK/ERK pathways in CD56^bright compared with CD56^dim NK cells, and blockade of these pathways attenuated antitumor responses. These findings identify CD56^bright NK cells as potent antitumor effectors that warrant further investigation as a cancer immunotherapy.

中文翻译：

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IL-15启动后，CD56^亮NK细胞表现出强大的抗肿瘤反应

NK细胞是先天免疫系统的淋巴细胞，对于防御传染性病原体和癌症很重要。经典地，认为CD56^暗NK细胞子集介导抗肿瘤反应，而CD56^亮子集参与免疫调节。在这里，我们通过证明用IL-15短暂引发显着增强CD56^亮NK细胞的抗肿瘤反应来挑战这种范例。引发改善了多种CD56^亮细胞功能：脱粒，细胞毒性和细胞因子产生。涂有底漆的CD56^明亮从白血病患者的细胞表现出增强的应答在体外自体爆炸，并引发CD56^明亮在鼠异种移植模型中，细胞可控制体内的白血病细胞。来自多发性骨髓瘤（MM）患者的初免CD56^亮细胞显示出对自体骨髓瘤靶点的优异反应，此外，来自MM患者体内用IL-15受体激动剂ALT-803引发的CD56^亮NK细胞显示出对MM的增强的离体功能反应目标。促成基于IL-15的启动的效应子机制包括改善的细胞毒性蛋白表达，靶细胞结合以及LFA-1，CD2-和NKG2D依赖性的NK细胞活化。最后，与CD56^昏暗相比，IL-15强烈刺激了CD56^明亮的PI3K / Akt / mTOR和MEK / ERK途径NK细胞以及对这些途径的阻断减弱了抗肿瘤反应。这些发现将CD56^亮NK细胞鉴定为有效的抗肿瘤效应子，值得作为癌症免疫疗法进行进一步研究。