乳腺癌细胞表达的HLA-G抑制NK细胞活性的分子机制研究

HLA-G belongs to nonclassical HLA class I molecules. Recently, many studies have demonstrated the overexpression of HLA-G in more than thirty type of tumor cells of epithelial origin including breast cancer, and the overexpression always correlated with poor prognosis of patients. Trastuzumab is the first monoclonal antibody that has been used for clinical treatment of HER2 positive breast carcinoma.Although its clinical therapeutic effect is satisfied, resistance still exist, and the mechanism of resistance are under debating. ADCC which conducted by NK cells have been reported playing key role in antitumor effects of Trastuzumab, and HLA-G can regulate the activity of NK cells by the interaction with its two receptors which expressed by NK cells:ILT2 and KIR2DL4. In previous study we have detected HLA-G expression level in patients who received Trastuzumab treatment and confirmed that HLA-G expressed by breast cancer cells can inhibited ADCC mediated by trastuzumab. In this topic we want to investigate the specific molecular mechanism of inhibition effccts of HLA-G on NK cells’ ADCC activity mediated by trastuzumab. This research are expected to provide new thread in clarification of trastuzumab resistance, and also supply new strategy for targeted therapy of breast cancer.

HLA-G属于非经典的HLAI类分子，研究发现其在乳腺癌在内的30多种肿瘤中过表达，并与不良预后相关。Trastuzumab是第一种用于HER2阳性乳腺癌临床治疗的单克隆抗体靶向药物，虽疗效显著但存在耐药，且耐药机制尚未完全阐明。研究发现NK细胞介导的ADCC在Trastuzumab 抗肿瘤过程中发挥关键作用，而HLA-G可通过与NK细胞表达的受体ILT2和KIR2DL4相互作用调节NK细胞的功能。本研究在前期工作中检测了HLA-G在Trastuzumab治疗乳腺癌患者中的表达水平，并已证实乳腺癌细胞高表达的HLA-G分子可明显抑制Trastuzumab介导的NK细胞的ADCC活性。本课题将在此工作基础上深入探讨HLA-G抑制Trastuzumab介导的NK细胞ADCC活性的具体分子机制，以期为Trastuzumab耐药机制的阐明提供新的思路，也为乳腺癌靶向治疗提供新的策略。

人类白细胞抗原(HLA)-G属于非经典的MHCI类分子，在母胎界面外滋养层细胞中表达，最初被报道主要参与母胎耐受，HLA-G是唯一已知的杀手细胞免疫球蛋白样受体2DL4(KIR2DL4)的配体，这是一种广泛表达于NK细胞表面的非典型家族分子，其发挥的作用目前尚存在争议。越来越多的研究发现，HLA-G是一种免疫检查点分子，在癌症免疫逃逸中具有特定的相关性，尽管HLA-G/KIR2DL4在抗肿瘤免疫中的作用仍不明确。我们之前的研究表明HLA-G是乳腺癌对曲妥珠单抗耐药的关键中介，阻断HLA-G/KIR2DL4相互作用可使乳腺癌对曲妥珠单抗治疗再敏感。本研究就HLA-G/KIR2DL4在乳腺癌免疫微环境中的作用进行探讨。更好地了解HLA-G有助于使其成为识别乳腺癌的新型生物标志物，这对乳腺癌患者的准确诊断和预后评估非常重要。此外，本研究阐明了HLA-G/KIR2DL4参与调控乳腺癌免疫微环境的机制，以期为联合HLA-G和免疫检查点靶向有效治疗乳腺癌提供理论依据。