Restoring NK cells functionality via cytokine activation enhances cetuximab-mediated NK-cell ADCC: A promising therapeutic tool for HCC patients.

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.

Interrupted Crosstalk between Natural Killer Cells and Anti-epidermal Growth Factor Receptor: A Possible Role in Hepatocellular Carcinoma Treatment Failure.

Hepatocellular carcinoma (HCC) is a major health problem worldwide. Most patients are diagnosed for the first time at late stages, which leads to very poor prognosis. It is challenging to discover strategies for treatment at these advanced stages. Recently, monoclonal antibodies (mAbs) targeting specific cellular signaling pathways in HCC have been developed. Unfortunately, they still have a low survival rate, and some of them failed clinically to produce effective responses even if they showed very good results against HCC in preclinical studies. This review focuses on and discusses the possible causes for the failure of mAbs, precisely anti-Epidermal Growth Factor Receptor (EGFR) mAb and the crosstalk between this mAb and patients' NK cells.