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.
Keywords:
ADCC; NK cell; NKG2D; breast cancer; docetaxel.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Antibodies, Blocking / immunology
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Antibodies, Blocking / pharmacology
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Antibody-Dependent Cell Cytotoxicity / drug effects*
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Antibody-Dependent Cell Cytotoxicity / genetics
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Antibody-Dependent Cell Cytotoxicity / immunology
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Antineoplastic Agents / administration & dosage
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Antineoplastic Agents / pharmacology
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Antineoplastic Combined Chemotherapy Protocols / pharmacology*
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Blotting, Western
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Breast Neoplasms / drug therapy*
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Breast Neoplasms / genetics
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Breast Neoplasms / immunology
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Bridged-Ring Compounds / administration & dosage
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Bridged-Ring Compounds / pharmacology
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Cell Line, Tumor
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Cells, Cultured
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Docetaxel
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Drug Synergism
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Female
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GPI-Linked Proteins / metabolism
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Gene Expression Regulation, Neoplastic / drug effects
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Histocompatibility Antigens Class I / metabolism
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Humans
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Intercellular Signaling Peptides and Proteins / metabolism
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Killer Cells, Natural / drug effects*
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Killer Cells, Natural / immunology
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Killer Cells, Natural / metabolism
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Mice, SCID
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NK Cell Lectin-Like Receptor Subfamily K / genetics
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NK Cell Lectin-Like Receptor Subfamily K / immunology*
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NK Cell Lectin-Like Receptor Subfamily K / metabolism
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Reverse Transcriptase Polymerase Chain Reaction
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Taxoids / administration & dosage
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Taxoids / pharmacology
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Trastuzumab / administration & dosage
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Trastuzumab / pharmacology
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Xenograft Model Antitumor Assays
Substances
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Antibodies, Blocking
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Antineoplastic Agents
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Bridged-Ring Compounds
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GPI-Linked Proteins
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Histocompatibility Antigens Class I
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Intercellular Signaling Peptides and Proteins
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KLRK1 protein, human
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MHC class I-related chain A
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NK Cell Lectin-Like Receptor Subfamily K
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Taxoids
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ULBP2 protein, human
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Docetaxel
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taxane
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Trastuzumab