Chemotherapy can enhance trastuzumab-mediated ADCC
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1
Fondazione IRCCS, Istituto Nazionale dei tumori, Dept. of Experimental Oncology and Molecular Medicine, Italy
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2
University of Milan, Department of Biomedical Science for Health, Italy
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3
Fondazione Istituto di Ricovero e Cura a Carattere Scientifico Policlinico San Matteo, Department of Infectious Diseases, Italy
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4
Fondazione IRCCS Istituto Nazionale dei Tumori of Milan, Department of Medical Oncology, Italy
Recent clinical data indicated a synergistic therapeutic effect between trastuzumab and taxanes in neoadjuvant setting in HER2-positive breast cancer patients. We hypothesized that the mechanism by which trastuzumab synergizes with taxanes might be mainly through ADCC and that it might depend on the ability of drug-induced stress to improve NK cell effectiveness.
A rapid and dynamic surface expression upmodulation of NK activator ligands was observed in HER2-positive BT474 and MDAMB361 breast carcinoma cell lines treated with taxotere both in vitro and in vivo, accompanied by about a 15-40% increase in in vitro trastuzumab-mediated ADCC. Consistently, antibodies blocking NK receptors (NKG2D and CD226) specific for these ligands significantly reduced this enhancement. We obtained PBMC from 8 HER2-positive breast carcinoma patients isolated at different time points during the neoadjuvant treatment protocol with taxanes followed by trastuzumab. Analysis of NK cells showed that even if their amount among PBMC decreased, their overall activation status increased after chemotherapy, resulting in in vitro ADCC levels on BT474 similar to those obtained with PBMC isolated before treatment. Notably NKG2D receptor on NK cells was significantly enhanced by chemotherapy treatment.
Altogether, our results indicate that taxanes can increase tumor susceptibility to ADCC acting on both tumor and NK cells, raising the possibility of identifying optimal chemotherapy administration schedules and new potential strategy to maximize trastuzumab-mediated ADCC.
(Partially supported by AIRC)
Keywords:
breast cancer,
ADCC,
trastuzumab,
NKG2D,
taxanes
Conference:
15th International Congress of Immunology (ICI), Milan, Italy, 22 Aug - 27 Aug, 2013.
Presentation Type:
Abstract
Topic:
Innate immunity
Citation:
Triulzi
T,
Sfondrini
L,
Varchetta
S,
Regondi
V,
Sasso
M,
Casalini
P,
Balsari
A,
Bianchi
G,
Mariani
G and
Tagliabue
E
(2013). Chemotherapy can enhance trastuzumab-mediated ADCC.
Front. Immunol.
Conference Abstract:
15th International Congress of Immunology (ICI).
doi: 10.3389/conf.fimmu.2013.02.00792
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Received:
13 Jun 2013;
Published Online:
22 Aug 2013.
*
Correspondence:
Dr. Elda Tagliabue, Fondazione IRCCS, Istituto Nazionale dei tumori, Dept. of Experimental Oncology and Molecular Medicine, Milan, Italy, elda.tagliabue@istitutotumori.mi.it