Mesothelin, a novel immunotherapy target for triple negative breast cancer.
Mesothelin, a novel immunotherapy target for triple negative breast cancer.
复制标题
DOI：
10.1007/s10549-012-2018-4
复制
发表时间：
2012-06
影响因子：
3.8
通讯作者：
Zhang PJ
中科院分区：
文献类型：
--
作者：
Tchou J;Wang LC;Selven B;Zhang H;Conejo-Garcia J;Borghaei H;Kalos M;Vondeheide RH;Albelda SM;June CH;Zhang PJ
间皮素是存在于间皮细胞上的一种细胞表面糖蛋白，在包括胰腺癌和卵巢癌在内的多种癌症中引起t细胞反应。乳腺癌不知道表达间皮素。我们假设间皮素可能是三阴性乳腺癌（TNBC）中一种独特的肿瘤相关抗原，TNBC是一种不太常见的乳腺癌亚型，在之前的研究中可能没有充分表征间皮素的表达。因此，我们使用福尔马林固定石蜡包埋档案肿瘤组织亚型，通过免疫组化分析筛选了99例原发性乳腺癌样本，证实间皮素在大多数TNBC（67%）中过表达，而在< 5%的ER（+）或Her2-neu（+）乳腺癌中则很少表达。为了确定间皮素是否可以作为一种新的乳腺癌免疫治疗靶点，研究人员进行了一项体外细胞杀伤试验，以比较表达间皮素特异性嵌合抗体受体（CAR）的基因修饰T细胞（mesoCAR T细胞）和非转导T细胞杀死表达间皮素的原发性乳腺癌细胞的能力。mesoCAR t细胞的抗肿瘤细胞毒性显著提高（31.7% vs. 8.7%, p<0.001）。我们的研究结果表明，间皮素有望成为迄今为止缺乏有效靶向治疗的TNBC的新免疫治疗靶点。
Mesothelin is a cell-surface glycoprotein present on mesothelial cells and elicits T-cell responses in a variety of cancers including pancreatic and ovarian cancer. Breast cancer is not known to express mesothelin. We postulated that mesothelin may be a unique tumor associated antigen in triple negative breast cancer (TNBC), a less common breast cancer subtype which may have been underrepresented in prior studies that characterized mesothelin expression. Therefore, we screened 99 primary breast cancer samples by immunohistochemistry analysis using formalin fixed paraffin embedded archival tumor tissues subtypes and confirmed that mesothelin was overexpressed in the majority of TNBC (67%) but only rarely in < 5% ER(+) or Her2-neu (+) breast cancer respectively. To determine whether mesothelin may be exploited as a novel immunotherapy target in breast cancer, an in vitro cell killing assay was performed to compare the ability of genetically modified T cells expressing a chimeric antibody receptor (CAR) specific for mesothelin (mesoCAR T-cells) or non-transduced T-cells to kill mesothelin-expressing primary breast cancer cells. A significantly higher anti-tumor cytotoxicity by mesoCAR T-cells was observed (31.7% vs. 8.7%, p<0.001). Our results suggest that mesothelin has promise as a novel immunotherapy target for TNBC for which effective targeted therapy is lacking to date.