Abstract
Recent clinical data indicate a synergistic therapeutic effect between trastuzumab and taxanes in neoadjuvantly treated HER2-positive breast cancer (BC) patients. In HER2+ BC experimental models and patients, we investigated whether this synergy depends on the ability of drug-induced stress to improve NK cell effectiveness and thus trastuzumab-mediated ADCC. HER2+ BC cell lines BT474 and MDAMB361 treated with docetaxel showed up-modulation of NK activator ligands both in vitro and in vivo, accompanied by a 15-40% increase in in vitro trastuzumab-mediated ADCC; antibodies blocking the NKG2D receptor significantly reduced this enhancement. NKG2D receptor expression was increased by docetaxel treatment in circulating and splenic NK cells from mice xenografted with tumor cells, an increase related to expansion of the CD11b+Ly6G+ cell population. Accordingly, NK cells derived from HER2+ BC patients after treatment with taxane-containing therapy expressed higher levels of NKG2D receptor than before treatment. Moreover, plasma obtained from these patients recapitulated the modulation of NKG2D on healthy donors' NK cells, improving their trastuzumab-mediated activity in vitro. This enhancement occurred mainly using plasma from patients with low NKG2D basal expression. Our results indicate that taxanes increase tumor susceptibility to ADCC by acting on tumor and NK cells, and suggest that taxanes concomitantly administered with trastuzumab could maximize the antibody effect, especially in patients with low basal immune effector cytotoxic activity.
Highlights
Trastuzumab, a recombinant humanized monoclonal antibody directed to the extracellular domain of the HER2 protein, is the paradigm of tailored treatment for patients with HER2-positive breast cancer
We report for the first time that taxanes significantly increase NK Group 2 member D (NKG2D) ligand expression on tumor cells and their susceptibility to natural killer (NK) activity
Docetaxel induces the expression of the activating cognate receptor NKG2D on NK cells, increasing their cytotoxic activity mediated by trastuzumab
Summary
Trastuzumab, a recombinant humanized monoclonal antibody directed to the extracellular domain of the HER2 protein, is the paradigm of tailored treatment for patients with HER2-positive breast cancer. Recent clinical data indicated a synergistic therapeutic effect between trastuzumab and chemotherapy in the neoadjuvant setting in these patients, with up to 70% pathological complete response [1] and especially when taxanes are used [2;3]. A key receptor for NK cell activation is NK Group 2 member D (NKG2D), a type II transmembrane C-type lectinlike receptor expressed on all NK cells. It binds multiple ligands, including MHC class I chain-related A (MICA), MICB and several UL-16 binding proteins (ULBPs), which are induced after cellular stress [12] and are the most common ligands for NK cell receptors in breast carcinomas together with DNAM-1 ligands [13]
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