Targeting of pre-existing and induced breast cancer stem cells with HER2-specific immunotherapeutics and NK cells (165.18)

Abstract Trastuzumab (Herceptin®) has substantially improved the overall survival of patients with mammary carcinoma. While recruitment of NK cells and antibody-dependent cell-mediated cytotoxicity (ADCC) contribute to this therapeutic effect, immunoselection of cultured breast cancer cells with trastuzumab and NK cells resulted in selective survival of individual sphere-forming cells. Moreover, epithelial to mesenchymal transition was induced which transformed previously differentiated cancer cells into cells with a CD44highCD24low “cancer stem cell-like” phenotype. Immunoselected breast cancer cells thus showed increased clonogenicity and differentiation potential in vitro and enhanced tumorigenicity in vivo. Their insufficient immunotherapeutic targeting might be due to low HER2 expression and the virtual absence of ligands for the activating NK cell receptors NKG2D and DNAM 1. Susceptibility towards NK cells and trastuzumab, however, was restored upon differentiation. Since relapse after antibody therapy could be due to such trastuzumab- and NK cell-refractory tumor initiating cells, we explored if treatment of these cells with the novel HER2-targeting drugs T-DM1 or the HER2 dimerisation inhibitor pertuzumab could improve NK cell mediated killing or counteract induction of the stem cell-like phenotype. This translational approach might help to identify the most promising drug candidate for the targeted second and third line treatment of HER2-positive metastasized breast cancer.