Clinical Collaboration Unit Translational Immunology, German Cancer Consortium (DKTK), Department of Internal Medicine, University Hospital Tübingen, Otfried-Müller-Str. 10, 72076 Tübingen, Germany.
Department of Women's Health, University Hospital Tübingen, Calwerstraße 7, 72076 Tübingen, Germany.
Int J Mol Sci. 2024 Apr 8;25(7):4126. doi: 10.3390/ijms25074126.
Ligands of the natural killer group 2D (NKG2DL) family are expressed on malignant cells and are usually absent from healthy tissues. Recognition of NKG2DLs such as MICA/B and ULBP1-3 by the activating immunoreceptor NKG2D, expressed by NK and cytotoxic T cells, stimulates anti-tumor immunity in breast cancer. Upregulation of membrane-bound NKG2DLs in breast cancer has been demonstrated by immunohistochemistry. Tumor cells release NKG2DLs via proteolytic cleavage as soluble (s)NKG2DLs, which allows for effective immune escape and is associated with poor prognosis. In this study, we collected serum from 140 breast cancer (BC) and 20 ductal carcinoma in situ (DCIS) patients at the time of initial diagnosis and 20 healthy volunteers (HVs). Serum levels of sNKG2DLs were quantified through the use of ELISA and correlated with clinical data. The analyzed sNKG2DLs were low to absent in HVs and significantly higher in BC patients. For some of the ligands analyzed, higher sNKG2DLs serum levels were associated with the classification of malignant tumor (TNM) stage and grading. Low sMICA serum levels were associated with significantly longer progression-free (PFS) and overall survival (OS). In conclusion, we provide the first insights into sNKG2DLs in BC patients and suggest their potential role in tumor immune escape in breast cancer. Furthermore, our observations suggest that serum sMICA levels may serve as a prognostic parameter in the patients analyzed in this study.
自然杀伤细胞组 2D（NKG2D）家族的配体在恶性细胞上表达，而在健康组织中通常不存在。NK 和细胞毒性 T 细胞表达的激活免疫受体 NKG2D 识别 MICA/B 和 ULBP1-3 等 NKG2DL，可刺激乳腺癌中的抗肿瘤免疫。免疫组织化学已证明乳腺癌中膜结合 NKG2DL 的上调。肿瘤细胞通过蛋白水解切割释放 NKG2DL 作为可溶性（s）NKG2DL，这允许有效的免疫逃逸，并与预后不良相关。在这项研究中，我们在初始诊断时收集了 140 名乳腺癌（BC）和 20 名导管原位癌（DCIS）患者以及 20 名健康志愿者（HV）的血清。通过 ELISA 定量测定血清 sNKG2DL 水平，并与临床数据相关联。HV 中的 sNKG2DL 水平较低或不存在，而 BC 患者中的 sNKG2DL 水平显著升高。对于分析的一些配体，较高的 sNKG2DL 血清水平与恶性肿瘤（TNM）分期和分级相关。低 sMICA 血清水平与显著更长的无进展生存期（PFS）和总生存期（OS）相关。总之，我们首次提供了关于 BC 患者 sNKG2DL 的见解，并表明它们在乳腺癌中的肿瘤免疫逃逸中具有潜在作用。此外，我们的观察结果表明，血清 sMICA 水平可能作为本研究中分析患者的预后参数。
