Petricevic Branka, Laengle Johannes, Singer Josef, Sachet Monika, Fazekas Judit, Steger Guenther, Bartsch Rupert, Jensen-Jarolim Erika, Bergmann Michael
Department of Surgery, Medical University of Vienna, Vienna General Hospital, Waehringer Guertel 18-20, Vienna A-1090, Austria.
J Transl Med. 2013 Dec 12;11:307. doi: 10.1186/1479-5876-11-307.
Monoclonal antibodies (mAb), such as trastuzumab are a valuable addition to breast cancer therapy. Data obtained from neoadjuvant settings revealed that antibody-dependent cell-mediated cytotoxicity (ADCC) is a major mechanism of action for the mAb trastuzumab. Conflicting results still call into question whether disease progression, prolonged treatment or concomitant chemotherapy influences ADCC and related immunological phenomena.
We analyzed the activity of ADCC and antibody-dependent cell-mediated phagocytosis (ADCP) of peripheral blood mononuclear cells (PBMCs) from human epidermal growth factor receptor 2 (HER2/neu) positive breast cancer patients receiving trastuzumab therapy either in an adjuvant (n = 13) or metastatic (n = 15) setting as well as from trastuzumab treatment-naive (t-naive) HER2/neu negative patients (n = 15). PBMCs from healthy volunteers (n = 24) were used as controls. ADCC and ADCP activity was correlated with the expression of antibody binding Fc-gamma receptor (FcγR)I (CD64), FcγRII (CD32) and FcγRIII (CD16) on CD14+ (monocytes) and CD56+ (NK) cells, as well as the expression of CD107a+ (LAMP-1) on CD56+ cells and the total amount of CD4+CD25+FOXP3+ (Treg) cells. In metastatic patients, markers were correlated with progression-free survival (PFS).
ADCC activity was significantly down regulated in metastatic, adjuvant and t-naive patient cohorts as compared to healthy controls. Reduced ADCC activity was inversely correlated with the expression of CD107a on CD56+ cells in adjuvant patients. ADCC and ADCP activity of the patient cohorts were similar, regardless of treatment duration or additional chemotherapy. PFS in metastatic patients inversely correlated with the number of peripheral Treg cells.
The reduction of ADCC in patients as compared to healthy controls calls for adjuvant strategies, such as immune-enhancing agents, to improve the activity of trastuzumab. However, efficacy of trastuzumab-specific ADCC and ADCP appears not to be affected by treatment duration, disease progression or concomitant chemotherapy. This finding supports the application of trastuzumab at any stage of the disease.
单克隆抗体（mAb），如曲妥珠单抗，是乳腺癌治疗中一项有价值的补充。从新辅助治疗环境中获得的数据显示，抗体依赖性细胞介导的细胞毒性（ADCC）是mAb曲妥珠单抗的主要作用机制。相互矛盾的结果仍使人质疑疾病进展、延长治疗或联合化疗是否会影响ADCC及相关免疫现象。
我们分析了接受曲妥珠单抗辅助治疗（n = 13）或转移性治疗（n = 15）的人表皮生长因子受体2（HER2/neu）阳性乳腺癌患者以及未接受过曲妥珠单抗治疗（初治）的HER2/neu阴性患者（n = 15）外周血单个核细胞（PBMC）的ADCC活性和抗体依赖性细胞介导的吞噬作用（ADCP）。来自健康志愿者（n = 24）的PBMC用作对照。ADCC和ADCP活性与CD14+（单核细胞）和CD56+（自然杀伤细胞）上抗体结合的Fc-γ受体（FcγR）I（CD64）、FcγRII（CD32）和FcγRIII（CD16）的表达相关，以及与CD56+细胞上CD107a+（溶酶体相关膜蛋白1）的表达和CD4+CD25+FOXP3+（调节性T细胞）的总量相关。在转移性患者中，标志物与无进展生存期（PFS）相关。
与健康对照相比，转移性、辅助性和初治患者队列中的ADCC活性显著下调。辅助性患者中ADCC活性降低与CD56+细胞上CD107a的表达呈负相关。无论治疗持续时间或是否进行额外化疗，患者队列的ADCC和ADCP活性相似。转移性患者的PFS与外周调节性T细胞数量呈负相关。
与健康对照相比，患者中ADCC的降低需要辅助策略，如免疫增强剂，以提高曲妥珠单抗的活性。然而，曲妥珠单抗特异性ADCC和ADCP的疗效似乎不受治疗持续时间、疾病进展或联合化疗的影响。这一发现支持在疾病的任何阶段应用曲妥珠单抗。
