Natural Killer (NK) cells are considered the first line of defense against viral infections and tumors. Several factors affect NK cytotoxic activity rendering it dysfunctional and thereby impeding the ability to scavenge abnormal cells as a part of immune escaping mechanisms induced by different types of cancers. NK cells play a crucial role augmenting the activity of various types of anticancer mAb since dysfunctional NK cells are the main reason for the low response to these therapies. To this light, we examined the phenotypic characters of the circulating NK cells isolated from HCC patients compared to healthy controls. Then, dysfunctional NK cells, from HCC patients, were reactivated with cytokines cocktail and their cytotoxic activity with the anti-EGFR mAb “cetuximab” was investigated. This showed a downregulation of patients NK cells activating receptors (NKP30, NKP46, NKG2D and CD16) as well as CD56 and up-regulation of NKG2A inhibitory receptor. We also reported an increase in aberrant CD56⁻ NK cells subset in peripheral blood of HCC patients compared to healthy controls. Thus, confirming the dysfunctionality of peripheral NK cells isolated from HCC patients. Cytokines re-activation of those NK cells lead to upregulation of NK activating receptors and downregulation of inhibitory receptor. Moreover, the percentage of aberrant CD56⁻ NK cells subset was reduced. Here, we proved that advanced HCC patients have an increased percentage of more immature and noncytotoxic NK cell subsets in their peripheral blood, which might account for the low cytotoxicity noticed in those patients. A significant improvement in the cytotoxicity against HCC was noticed upon using reactivated NK cells combined with cetuximab. Therefore, this study highlights the potential recruitment of NK immune cells along with cetuximab to enhance cytotoxicity against HCC.

自然杀伤 (NK) 细胞被认为是抵御病毒感染和肿瘤的第一道防线。有几个因素会影响 NK 细胞毒活性，使其功能失调，从而阻碍清除异常细胞的能力，这是不同类型癌症诱导的免疫逃逸机制的一部分。NK 细胞在增强各种类型抗癌 mAb 的活性方面起着至关重要的作用，因为功能失调的 NK 细胞是对这些疗法的低反应的主要原因。为此，我们检查了从 HCC 患者中分离出的循环 NK 细胞与健康对照相比的表型特征。然后，来自 HCC 患者的功能失调的 NK 细胞用细胞因子混合物重新激活，并研究了它们与抗 EGFR mAb“西妥昔单抗”的细胞毒活性。这表明患者 NK 细胞激活受体（NKP30、NKP46、NKG2D 和 CD16）以及 CD56 的下调和 NKG2A 抑制性受体的上调。我们还报告了异常 CD56⁻与健康对照相比，HCC 患者外周血中的 NK 细胞亚群。因此，证实了从 HCC 患者中分离的外周 NK 细胞的功能障碍。这些 NK 细胞的细胞因子重新激活导致 NK 激活受体的上调和抑制性受体的下调。此外，异常 CD56 的百分比^-NK细胞亚群减少。在这里，我们证明晚期 HCC 患者外周血中未成熟和非细胞毒性 NK 细胞亚群的百分比增加，这可能解释了在这些患者中注意到的低细胞毒性。使用重新激活的 NK 细胞与西妥昔单抗联合使用时，注意到对 HCC 的细胞毒性有显着改善。因此，这项研究强调了 NK 免疫细胞与西妥昔单抗的潜在募集以增强对 HCC 的细胞毒性。