Department of Oncology-Pathology, Karolinska Institute, Radiumhemmet, Karolinska University Hospital, Stockholm, Sweden.
Cancer Immunol Immunother. 2012 Aug;61(8):1243-53. doi: 10.1007/s00262-012-1201-0. Epub 2012 Jan 19.
In recent years, evidence is accumulating that cancer cells develop strategies to escape immune recognition. HLA class I HC down-regulation is one of the most investigated. In addition, different HLA haplotypes are known to correlate to both risk of acquiring diseases and also prognosis in survival of disease or cancer. We have previously shown that patients with serous adenocarcinoma of the ovary in advanced surgical stage disease have a particularly poor prognosis if they carry the HLA-A02* genotype. We aimed to study the relationship between HLA-A02* genotype in these patients and the subsequent HLA class I HC protein product defects in the tumour tissue.
One hundred and sixty-two paraffin-embedded tumour lesions obtained from Swedish women with epithelial ovarian cancer were stained with HLA class I heavy chain (HC) and β(2)-microglobulin (β(2)-m)-specific monoclonal antibodies (mAb). Healthy ovary and tonsil tissue served as a control. The HLA genotype of these patients was determined by PCR/sequence-specific primer method. The probability of survival was calculated using the Kaplan-Meier method, and the hazard ratio (HR) was estimated using proportional hazard regression.
Immunohistochemical staining of ovarian cancer lesions with mAb showed a significantly higher frequency of HLA class I HC and β(2)-m down-regulation in patients with worse prognosis (WP) than in those with better prognosis. In univariate analysis, both HLA class I HC down-regulation in ovarian cancer lesions and WP were associated with poor survival. In multivariate Cox-analysis, the WP group (all with an HLA-A02* genotype) had a significant higher HR to HLA class I HC down-regulation.
HLA-A02* is a valuable prognostic biomarker in epithelial ovarian cancer. HLA class I HC loss and/or down-regulation was significantly more frequent in tumour tissues from HLA-A02* positive patients with serous adenocarcinoma surgical stage III-IV. In multivariate analysis, we show that the prognostic impact is reasonably correlated to the HLA genetic rather than to the expression of its protein products.
近年来，越来越多的证据表明癌细胞会发展出逃避免疫识别的策略。HLA Ⅰ类重链（HC）下调就是其中研究最多的一种。此外，不同的 HLA 单倍型与疾病的发病风险以及疾病或癌症的生存预后都相关。我们先前的研究显示，晚期手术期浆液性腺癌患者如果携带 HLA-A02基因型，其预后尤其差。本研究旨在探讨这些患者 HLA-A02基因型与肿瘤组织中 HLA Ⅰ类 HC 蛋白产物缺陷之间的关系。
我们对 162 例瑞典上皮性卵巢癌患者的石蜡包埋肿瘤组织进行了 HLA-A02*基因型分析，并用 HLA Ⅰ类 HC 和 β2-微球蛋白（β2-m）特异性单克隆抗体（mAb）进行了染色。健康卵巢和扁桃体组织作为对照。采用聚合酶链反应/序列特异性引物方法确定这些患者的 HLA 基因型。采用 Kaplan-Meier 法计算生存率，采用比例风险回归法估计危险比（HR）。
用 mAb 对卵巢癌组织进行免疫组化染色显示，预后较差（WP）患者的 HLA Ⅰ类 HC 及β2-m 下调频率显著高于预后较好患者。单因素分析显示，卵巢癌组织 HLA Ⅰ类 HC 下调和 WP 均与生存不良相关。多因素 Cox 分析显示，WP 组（均为 HLA-A02*基因型）的 HLA Ⅰ类 HC 下调 HR 显著更高。
HLA-A02是上皮性卵巢癌有价值的预后生物标志物。HLA-A02阳性、浆液性腺癌Ⅲ-Ⅳ期手术期患者肿瘤组织中 HLA Ⅰ类 HC 缺失和/或下调更为常见。多因素分析显示，其预后影响与 HLA 基因相关，而非与其蛋白产物的表达相关。
