Aromatase inhibitors increase the sensitivity of human tumor cells to monocyte-mediated, antibody-dependent cellular cytotoxicity
Aromatase inhibitors increase the sensitivity of human tumor cells to monocyte-mediated, antibody-dependent cellular cytotoxicity
复制标题
DOI：
10.1016/j.amjsurg.2005.06.013
复制
发表时间：
2005-10-01
影响因子：
3
通讯作者：
Parker, J
中科院分区：
文献类型：
--
作者：
Braun, DP;Crist, KA;Parker, J
目的：乳腺癌疫苗Theratope（Biomira Corporation，埃德蒙顿，阿尔伯塔，加拿大）的一项随机、安慰剂对照III期试验显示，与激素治疗加对照疫苗治疗的患者相比，激素治疗加对照疫苗治疗的患者存活时间明显更长。本研究的目的是阐明一种机制来解释这种影响。方法：对以雌激素受体（ER）、STn和粘蛋白-1（Muc 1）表达为特征的肿瘤细胞进行预处理（24小时）与芳香酶抑制剂（AI）福美司坦，随后使用Cr-51-B12抗体（Abs）评估在存在和不存在STn或Muc 1抗体（Abs）的情况下对单核细胞介导的杀伤的敏感性。结果：培养在培养基中的ER+/STn+/Muc 1+肿瘤细胞在STn和Muc 1 Ab不存在或存在下对单核细胞杀伤同样敏感（平均值分别为54%和55%，P =.不显著）。福美司坦预处理的细胞显示在不存在Ab的情况下对单核细胞杀伤的敏感性降低（平均值= 45%细胞溶解，P = 0.07），但对单核细胞介导的抗体依赖性细胞毒性（MM-ADCC）的敏感性显著增加（平均值= 65%，P = 0.003）。这些效果都没有看到与ER+/STn-/Muc 1+细胞或ER-/STn+/Muc 1+细胞，表明需要ER和STn阳性的靶肿瘤cells.Conclusions：肿瘤细胞与AI治疗表现出增加的敏感性MM-ADCC。AI使肿瘤细胞对这种形式的抗肿瘤免疫“敏感”的能力代表了迄今为止未描述的机制，其中基于肿瘤的治疗可以与抗原特异性肿瘤免疫协作，以在转移性乳腺癌患者中产生改善的体内肿瘤控制。(c)2005 Excerpta Medica Inc. All rights reserved.
Objective: A randomized, placebo-controlled phase III trial of the breast cancer vaccine Theratope (Biomira Corporation, Edmonton, Alberta, Canada), which expresses the underglycosylated, mucin-associated peptide STn showed that patients treated concomitantly with hormone therapy plus vaccine survived significantly longer than patients treated with hormone therapy plus a control vaccine. The objective of this study was to elucidate a mechanism to explain this effect.Methods: Tumor cells characterized for expression of estrogen receptor (ER), STn, and Mucin-1 (Muc1) were pretreated (24 hours) with the aromatase inhibitor (AI) formestane, followed by assessment of sensitivity to monocyte mediated killing in the presence and absence of STn or Muc1 antibodies (Abs) using the Cr-51-release assay.Results: ER+/STn+/Mucl + tumor cell's cultured in medium were equally sensitive to killing by monocytes in the absence or presence of STn and Muc1 Abs (mean = 54% and 55% cytolysis, respectively, P =. not significant). Formestane-pretreated cells showed decreased sensitivity to killing by monocytes in the absence of Abs (mean = 45% cytolysis, P = .07) but significantly increased sensitivity to monocyte-mediated, antibody-dependent cellular cytotoxicity (MM-ADCC) (mean = 65%, P = .003). These effects were not seen with either ER+/STn-/Muc1 + cells or ER-/STn+/Muc1 + cells, indicating the need for both ER and STn positivity of the target tumor cells.Conclusions: Tumor cells treated with an AI exhibit increased sensitivity to MM-ADCC. The capacity of an AI to "sensitize" tumor cells to this form of antitumor immunity represents a heretofore, undescribed mechanism whereby a hormone-based treatment may collaborate with antigen-specific tumor immunity to produce improved tumor control in vivo in metastatic breast cancer patients. (c) 2005 Excerpta Medica Inc. All rights reserved.