Department of Gynecologic Oncology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
Int J Cancer. 2012 Oct 15;131(8):1828-36. doi: 10.1002/ijc.27449. Epub 2012 Mar 9.
Tumor cells can escape from cytotoxic T-cell responses by downregulation of human leukocyte antigen (HLA) class I molecules expressed at the cell surface which has been associated with a deficient mismatch repair (MMR) system in colorectal carcinomas. Our study investigated the association between expression of MMR proteins and HLA class I in sporadic endometrioid endometrial carcinomas (EC). In a consecutively selected cohort of 486 EC patients, MMR proteins (MLH1, MSH2 and MSH6) and HLA class I (HLA-A, -B, -C or β(2) m) were investigated by immunohistochemistry. Expression levels of MMR proteins and HLA class I were compared between low-grade and high-grade ECs. HLA class I expression was compared between tumors with loss (negative immunostaining of ≥1 MMR protein) and expression of MMR proteins. Associations between previously determined numbers of intratumoral CD8(+) T-lymphocytes and expression of MMR proteins and HLA class I and the influence on survival was determined. ECs with loss of MMR protein expression (33.5%) more frequently have loss of HLA-B/C (37.3%), compared to ECs with MMR protein expression (25.5%, p = 0.007). Patients with loss of MMR proteins have a worse disease-specific survival compared to patients with expression (p = 0.039). CD8(+) T-lymphocytes have a positive influence on disease-free and disease-specific survival in the total EC cohort but not in patients with loss of MMR protein expression. In conclusion, our results indicate that loss of MMR protein expression is related to selective downregulation of HLA class I which contributes to immune escape in EC with an abnormal MMR system.
肿瘤细胞可以通过下调细胞表面表达的人类白细胞抗原（HLA）I 类分子来逃避细胞毒性 T 细胞反应，这与结直肠癌中错配修复（MMR）系统缺陷有关。我们的研究调查了散发性子宫内膜样腺癌（EC）中 MMR 蛋白和 HLA I 类表达之间的关系。在连续选择的 486 例 EC 患者队列中，通过免疫组织化学检测 MMR 蛋白（MLH1、MSH2 和 MSH6）和 HLA I 类（HLA-A、-B、-C 或β（2）m）。比较低级别和高级别 EC 之间的 MMR 蛋白和 HLA I 类的表达水平。比较 HLA I 类表达与 MMR 蛋白缺失（≥1 种 MMR 蛋白免疫染色阴性）和 MMR 蛋白表达之间的关系。还确定了肿瘤内 CD8+T 淋巴细胞的数量与 MMR 蛋白和 HLA I 类表达之间的关系及其对生存的影响。与 MMR 蛋白表达的 EC 相比，MMR 蛋白缺失的 EC 更频繁地缺失 HLA-B/C（37.3%，比 25.5%，p=0.007）。与表达 MMR 蛋白的患者相比，MMR 蛋白缺失的患者疾病特异性生存率更差（p=0.039）。CD8+T 淋巴细胞对总 EC 队列的无病生存和疾病特异性生存有积极影响，但对 MMR 蛋白缺失的患者没有影响。总之，我们的研究结果表明，MMR 蛋白缺失与 HLA I 类的选择性下调有关，这有助于异常 MMR 系统的 EC 中的免疫逃逸。
