title: Taxanes enhance trastuzumab-mediated ADCC on tumor cells through NKG2D-mediated NK cell recognition.
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.
authors.affiliation: Molecular Targeting Unit, Department of Experimental Oncology and Molecular Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
authors.forename: Martina
authors.initials: M
authors.lastname: Di Modica
authors.affiliation: Dipartimento di Scienze Biomediche per la Salute, Università degli Studi di Milano, Milan, Italy.
authors.forename: Lucia
authors.initials: L
authors.lastname: Sfondrini
authors.affiliation: Molecular Targeting Unit, Department of Experimental Oncology and Molecular Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
authors.forename: Viola
authors.initials: V
authors.lastname: Regondi
authors.affiliation: Department of Infectious Diseases, Fondazione Istituto di Ricovero e Cura a Carattere Scientifico Policlinico San Matteo, Pavia, Italy.
authors.forename: Stefania
authors.initials: S
authors.lastname: Varchetta
authors.affiliation: Department of Infectious Diseases, Fondazione Istituto di Ricovero e Cura a Carattere Scientifico Policlinico San Matteo, Pavia, Italy.
authors.forename: Barbara
authors.initials: B
authors.lastname: Oliviero
authors.affiliation: Department of Medical Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
authors.forename: Gabriella
authors.initials: G
authors.lastname: Mariani
authors.affiliation: Department of Medical Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
authors.forename: Giulia Valeria
authors.initials: GV
authors.lastname: Bianchi
authors.affiliation: Dipartimento di Terapia Molecolare e Farmacogenomica, Istituti Ospitalieri di Cremona, Cremona, Italy.
authors.forename: Daniele
authors.initials: D
authors.lastname: Generali
authors.affiliation: Molecular Targeting Unit, Department of Experimental Oncology and Molecular Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.|Dipartimento di Scienze Biomediche per la Salute, Università degli Studi di Milano, Milan, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Balsari
authors.affiliation: Molecular Targeting Unit, Department of Experimental Oncology and Molecular Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
authors.forename: Tiziana
authors.initials: T
authors.lastname: Triulzi
authors.affiliation: Molecular Targeting Unit, Department of Experimental Oncology and Molecular Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
authors.forename: Elda
authors.initials: E
authors.lastname: Tagliabue
mesh_terms: D000818:Animals; D019138:Antibodies, Blocking / Q000276:immunology / Q000494:pharmacology; D000920:Antibody-Dependent Cell Cytotoxicity / Q000187:drug effects* / Q000235:genetics / Q000276:immunology; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000494:pharmacology; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000276:immunology; D001952:Bridged-Ring Compounds / Q000008:administration & dosage / Q000494:pharmacology; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D000077143:Docetaxel; D004357:Drug Synergism; D005260:Female; D058851:GPI-Linked Proteins / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D015395:Histocompatibility Antigens Class I / Q000378:metabolism; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism; D007694:Killer Cells, Natural / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D016513:Mice, SCID; D055655:NK Cell Lectin-Like Receptor Subfamily K / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D043823:Taxoids / Q000008:administration & dosage / Q000494:pharmacology; D000068878:Trastuzumab / Q000008:administration & dosage / Q000494:pharmacology; D023041:Xenograft Model Antitumor Assays
chemical_list: D019138:Antibodies, Blocking; D000970:Antineoplastic Agents; D001952:Bridged-Ring Compounds; D058851:GPI-Linked Proteins; D015395:Histocompatibility Antigens Class I; D036341:Intercellular Signaling Peptides and Proteins; C527085:KLRK1 protein, human; C099187:MHC class I-related chain A; D055655:NK Cell Lectin-Like Receptor Subfamily K; D043823:Taxoids; C423230:ULBP2 protein, human; D000077143:Docetaxel; C080625:taxane; D000068878:Trastuzumab
keywords: ADCC; NK cell; NKG2D; breast cancer; docetaxel