Tumor-Derived α-Fetoprotein Directly Drives Human Natural Killer–Cell Activation and Subsequent Cell Death

Abstract

Hepatocellular carcinoma (HCC) patients with reduced natural killer (NK)-cell numbers and function have been shown to have a poor disease outcome. Mechanisms underlying NK-cell deficiency and dysfunction in HCC patients remain largely unresolved. α-Fetoprotein (AFP) is an oncofetal antigen produced by HCC. Previous studies demonstrated that tumor-derived AFP (tAFP) can indirectly impair NK-cell activity by suppressing dendritic cell function. However, a direct tAFP effect on NK cells remains unexplored. The purpose of this study was to examine the ability of cord blood-derived AFP (nAFP) and that of tAFP to directly modulate human NK-cell activity and longevity Short-term exposure to tAFP and, especially, nAFP proteins induced a unique proinflammatory, IL2-hyperresponsive phenotype in NK cells as measured by IL1β, IL6, and TNF secretion, CD69 upregulation, and enhanced tumor cell killing. In contrast, extended coculture with tAFP, but not nAFP, negatively affected long-term NK-cell viability. NK-cell activation was directly mediated by the AFP protein itself, whereas their viability was affected by hydrophilic components within the low molecular mass cargo that copurified with tAFP. Identification of the distinct impact of circulating tAFP on NK-cell function and viability may be crucial to developing a strategy to ameliorate HCC patient NK-cell functional deficits..

From bench to bed: the tumor immune microenvironment and current immunotherapeutic strategies for hepatocellular carcinoma

“…A recent study also indicates AFP may exert dual effects on NK cells functions in a direct manner. Short-term exposure to AFP induces IL-2 hyperresponsive phenotype NK cells, accompanied with elevated secretion of IL-1β, IL-6 and TNF-α [82]. These pro-inflammatory cytokines were associated with a low recurrence rate and a prolonged overall survival (OS) of HBV-related HCC patients [83].…”

Hepatocellular cancer-derived alpha fetoprotein uptake reduces CD1 molecules on monocyte-derived dendritic cells

“…DC derived from monocytes cultured in the presence of AFP (both tAFP and nAFP) stimulated T cells with a lower level of proliferation, in both a mixed lymphocyte reaction (MLR), and in an influenza-specific T cell recall response assay [3]. More recently, we found that AFP can impact the ability of human dendritic cells (DC) to stimulate NK cells [4], resulting in altered cytokine production and decreased NK cell viability.…”

Non-secretion of AFP and neutrophil lymphocyte ratio as predictors for survival in hepatocellular carcinoma patients treated with sorafenib: a large UK cohort

“…Whilst prospective validation of this finding is needed, this association may in part explain the better prognosis of patients with HCC who do not secrete AFP. Recent in vitro studies have demonstrated that tumour-derived AFP can directly impair natural killer (NK) cell activation and viability [ 32 ], indirectly impair NK cell activity through suppression of dendritic cell function [ 33 ], and induce aberrant dendritic cell differentiation with consequential reduction in the secretion of inflammatory cytokines and chemokines and limited T cell activation [ 34 , 35 ]. Thus shifting the balance towards a high NLR in the presence of AFP.…”