Taxanes enhance trastuzumab-mediated ADCC on tumor cells through NKG2D-mediated NK cell recognition

Abstract

// Martina Di Modica 1, * , Lucia Sfondrini 2, * , Viola Regondi 1 , Stefania Varchetta 3 , Barbara Oliviero 3 , Gabriella Mariani 4 , Giulia Valeria Bianchi 4 , Daniele Generali 5 , Andrea Balsari 1, 2 , Tiziana Triulzi 1, * , Elda Tagliabue 1, * 1 Molecular Targeting Unit, Department of Experimental Oncology and Molecular Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy 2 Dipartimento di Scienze Biomediche per la Salute, Università degli Studi di Milano, Milan, Italy 3 Department of Infectious Diseases, Fondazione Istituto di Ricovero e Cura a Carattere Scientifico Policlinico San Matteo, Pavia, Italy 4 Department of Medical Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy 5 Dipartimento di Terapia Molecolare e Farmacogenomica, Istituti Ospitalieri di Cremona, Cremona, Italy * These authors have contributed equally to this work Correspondence to: Elda Tagliabue, e-mail: elda.tagliabue@istitutotumori.mi.it Keywords: breast cancer, docetaxel, ADCC, NK cell, NKG2D Received: October 28, 2015      Accepted: November 09, 2015      Published: November 21, 2015 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.