Immunosuppressive factors, such as soluble major histocompatibility complex class I chain-related
peptide A (sMICA) and
transforming growth factor beta 1 (TGF-β1), are involved in tumor immune escape mechanisms (TIEMs) exhibited by
head and neck squamous cell carcinomas (HNSCCs) and may represent opportunities for therapeutic intervention. In order to overcome TIEMs, we investigated the antibody-dependent cellular cytotoxicity (ADCC),
cytokine release and retargeted
tumor infiltration of sMICA-inhibited patient NK cells expressing Fcγ receptor IIIa (FcγRIIIa, CD16a) in the presence of
cetuximab, an anti-
epidermal growth factor receptor (HER1)
monoclonal antibody (mAb). Compared to healthy controls, relapsed
HNSCC patients (n = 5), not currently in treatment revealed decreased levels of circulating regulatory NK cell subsets in relation to increased cytotoxic NK cell subpopulations. Elevated sMICA and TGF-β1 plasma levels correlated with diminished TNFα and IFN-γ release and decreased NKG2D (natural killer group 2 member D)-dependent killing of
HNSCC cells by NK cells. Incubation of IL-2-activated patient NK cells with patient plasma containing elevated sMICA or sMICA analogs (shed
MICA and recombinant
MICA) significantly impaired NKG2D-mediated killing by down-regulation of NKG2D surface expression. Of note, CD16 surface expression levels, pro-apoptotic and activation markers, and viability of patient and healthy donor NK cell subpopulations were not affected by this treatment. Accordingly,
cetuximab restored killing activity of sMICA-inhibited patient NK cells against
cetuximab-coated primary
HNSCC cells via ADCC in a dose-dependent manner. Rapid reconstitution of anti-
tumor recognition and enhanced
tumor infiltration of treated NK cells was monitored by 24 h co-incubation of
HNSCC tumor spheroids with
cetuximab (1 μg/ml) and was characterized by increased IFN-γ and TNFα secretion. This data show that the impaired NK cell-dependent
tumor surveillance in relapsed
HNSCC patients could be reversed by the re-establishment of ADCC-mediated effector cell activity, thus supporting NK cell-based
immunotherapy in combination with
antineoplastic monoclonal mAbs.