Abstract 1077: Loss of HER2 via trogocytosis by CD14+ cells in HER2-overexpressing breast cancer cells is associated with diminishing of trastuzumab-mediated antibody-dependent cellular cytotoxicity

Abstract

Abstract The transfer of cell-surface membrane proteins and membrane patches from one cell to another at the time of contact, known as trogocytosis, was reported in chronic lymphocytic leukemia and multiple myeloma patients and was associated with clinical outcome. However, in solid malignant tumors, such as breast cancer, there is no evidence that trogocytosis occurs clinically thus its clinical importance has not been evaluated yet. In the current study, we found significantly high HER2 expression on tumor-infiltrated CD14+ cells as compared to control CD14+ cells of PBMCs in HER2 overexpressing breast cancer patient who had been treated with trastuzmab. Digested tumor cell suspension and its autologous PBMCs were co-cultured at 1:10 ratio with 0 and 1 μg/ml of trastuzumab as trogocytosis assay. Percentage of HER2 positive CD14+ cells was higher in the treatment of 1 μg/ml of trastuzumab as compared to that of 0 μg/ml of trastuzumab (17% and 12%, respectively) while HER2 expression of digested tumor cells was lower in 1 μg/ml of trastuzumab treatment as compared to that of 0 μg/ml of trastuzumab (18% and 25%, respectively). These findings suggested that HER2 might be transferred from HER2 overexpressing breast tumor cells to CD14+ cells, which was possibility of evidence of trogocytosis in the HER2+ breast cancer patient, and suggested that CD14+ cell might have an important role in the trogocytosis. We next define the role of CD14+ cells and CD56+ cells in the process of both trogocytosis and antibody dependent cellular cytotoxicity (ADCC) in experimental setting using SK-BR-3 and BT-474, both HER2 overexpressing human breast cancer cell lines, and MCF-7 and MDA-MB-231, both HER2 negative human breast cancer cell lines. We found that trogocytosis was observed specifically on HER2 overexpressing breast cancer cell lines in in vitro torogocytosis assay and CD14+ cells have a role for trogocytosis dominantly as compared to CD56+ cells. HER2 loss was increased as Effector / Target ratio or concentration of trastuzumab was increased. HER2 loss on target cancer cells caused by trogocytosis of CD14+ cells inhibits CD56+ cell-mediated ADCC, however when CD14+ cells are depleted, such inhibitory effects are recovered and CD56+ cells show better cytotoxicity. Currently analyzed preliminary clinical sample data and experimental data of HER2 loss via trogocytosis might explain different level of treatment response of trastuzumab in individual patients. Citation Format: Eiji Suzuki, Mariko Nishie, Kosuke Kawaguchi, Sunao Tanaka, Masakazu Toi. Loss of HER2 via trogocytosis by CD14+ cells in HER2-overexpressing breast cancer cells is associated with diminishing of trastuzumab-mediated antibody-dependent cellular cytotoxicity. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1077. doi:10.1158/1538-7445.AM2014-1077