Ling Agnes, Löfgren-Burström Anna, Larsson Pär, Li Xingru, Wikberg Maria L, Öberg Åke, Stenling Roger, Edin Sofia, Palmqvist Richard
Department of Medical Biosciences, Pathology, Umeå University, Umeå, Sweden.
Department of Surgical and Perioperative Sciences, Surgery, Umeå University, Umeå, Sweden.
Oncoimmunology. 2017 Aug 7;6(11):e1356143. doi: 10.1080/2162402X.2017.1356143. eCollection 2017.
The anti-tumor immune response has been shown to be of great prognostic importance in colorectal cancer (CRC) and so has the tumors ability for immune evasion. Our aim of this study was to investigate tumor factors that influence immunity. We used a gene expression array to search for potential mechanisms of tumor immune escape. One candidate gene identified was , involved in antigen presentation by MHC class I. TAP1 protein expression was evaluated by immunohistochemistry in 436 CRC patients of the Colorectal Cancer in Umeå Study cohort. We found a significant association between a downregulated expression of TAP1 and low infiltration of various subtypes of lymphocytes as well as macrophages. A downregulated expression of TAP1 was further found to be independent of molecular characteristics, suggesting TAP1 down-regulation to reach beyond the well described highly immunogenic MSI CRCs. A low expression of TAP1 was also significantly associated with poor prognosis in patients with CRC, a result that stayed significant in tumor front of early stage tumors (stage I-II) through multivariable analyses. Furthermore, we found that TAP1 expression was inversely correlated with methylation at sites in close proximity to the promoter region. In summary, our results show down-regulation of TAP1 to be a general mechanism of tumor immune escape in CRC and a poor prognostic factor in stage I-II CRC patients. We also suggest that methylation of the gene may be a putative mechanism for TAP1 downregulation.
抗肿瘤免疫反应已被证明在结直肠癌（CRC）中具有重要的预后意义，肿瘤的免疫逃逸能力也是如此。本研究的目的是调查影响免疫的肿瘤因素。我们使用基因表达阵列来寻找肿瘤免疫逃逸的潜在机制。鉴定出的一个候选基因是 ，它参与MHC I类分子的抗原呈递。通过免疫组织化学在乌梅奥结直肠癌研究队列的436例CRC患者中评估了TAP1蛋白表达。我们发现TAP1表达下调与各种淋巴细胞亚型以及巨噬细胞的低浸润之间存在显著关联。进一步发现TAP1表达下调与分子特征无关，这表明TAP1下调不仅限于已充分描述的高免疫原性微卫星高度不稳定（MSI）CRC。TAP1低表达也与CRC患者的不良预后显著相关，通过多变量分析，这一结果在早期肿瘤（I-II期）的肿瘤前沿仍然显著。此外，我们发现TAP1表达与启动子区域附近位点的甲基化呈负相关。总之，我们的结果表明TAP1下调是CRC中肿瘤免疫逃逸的一般机制，也是I-II期CRC患者的不良预后因素。我们还认为 基因的甲基化可能是TAP1下调的一种推定机制。
