HER2/HER3 Signaling Regulates NK Cell-Mediated Cytotoxicity via MHC Class I Chain-Related Molecule A and B Expression in Human Breast Cancer Cell Lines
HER2/HER3 Signaling Regulates NK Cell-Mediated Cytotoxicity via MHC Class I Chain-Related Molecule A and B Expression in Human Breast Cancer Cell Lines
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DOI：
10.4049/jimmunol.1102237
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发表时间：
2012-03-01
影响因子：
4.4
通讯作者：
Kiessling, Rolf
中科院分区：
文献类型：
--
作者：
Okita, Riki;Mougiakakos, Dimitrios;Kiessling, Rolf
受体酪氨酸激酶HER2和HER3的过表达与几种癌症的不良预后相关。目前，her2和her3靶向治疗正在临床实践中或在临床试验中进行评估，包括使用单克隆抗体介导生长抑制和/或激活抗体诱导的先天或适应性细胞免疫。因此，有必要更好地了解肿瘤中HER2/HER3信号如何影响细胞免疫机制。在本研究中，我们证明了HER2/HER3信号通路在乳腺癌细胞系中调控MHC i类相关链A和B （MICA和MICB）的表达。MICA和MICB （MICA/B）分子作为激活受体NK组2成员D （NKG2D）的关键配体，促进NK细胞介导的识别和细胞溶解。HER3基因沉默而非HER2基因沉默可下调MICA/B的表达，HER3基因过表达可显著增强MICA的表达。在HER2/HER3信号激活的主要通路中，PI3K/AKT通路被证明主要调控MICA/B的表达。用HER3特异性配体神经调节蛋白1 β (neuregulin 1 β)治疗可促进HER3的表达，该过程可被HER3的药理学和遗传干扰所拮抗，但不能被ataxa -毛细血管扩张突变（ATM）以及ATM和rad3相关蛋白激酶抑制剂咖啡因所拮抗。这些观察结果进一步强调了HER2/HER3信号直接调节MICA/B的表达，而不是通过基因毒性应激。正如预期的那样，刺激HER2/HER3增强了NKG2D-MICA/ b依赖性NK细胞介导的细胞毒性。综上所述，我们得出结论，乳腺癌细胞系中通过HER2/HER3通路的信号传导可能导致NK细胞和T细胞对NKG2D-MICA/B的识别增强。免疫学杂志，2012,18(8):2136-2145。
Overexpression of the receptor tyrosine kinases HER2 and HER3 is associated with a poor prognosis in several types of cancer. Presently, HER2-as well as HER3-targeted therapies are in clinical practice or evaluated within clinical trials, including treatment with mAbs mediating growth inhibition and/or activation of Ab-induced innate or adaptive cellular immunity. A better understanding of how HER2/HER3 signaling in tumors influences cellular immune mechanisms is therefore warranted. In this study, we demonstrate that HER2/HER3 signaling regulates the expression of MHC class I-related chain A and B (MICA and MICB) in breast cancer cell lines. The MICA and MICB (MICA/B) molecules act as key ligands for the activating receptor NK group 2, member D (NKG2D) and promote NK cell-mediated recognition and cytolysis. Genetic silencing of HER3 but not HER2 downregulated the expression of MICA/B, and HER3 overexpression significantly enhanced MICA expression. Among the major pathways activated by HER2/HER3 signaling, the PI3K/AKT pathway was shown to predominantly regulate MICA/B expression. Treatment with the HER3-specific ligand neuregulin 1 beta promoted the expression in a process that was antagonized by pharmacological and genetic interference with HER3 but not by the ataxia-telangiectasia-mutated (ATM) and ATM and Rad3-related protein kinases inhibitor caffeine. These observations further emphasize that HER2/HER3 signaling directly, and not via genotoxic stress, regulates MICA/B expression. As anticipated, stimulating HER2/HER3 enhanced the NKG2D-MICA/B-dependent NK cell-mediated cytotoxicity. Taken together, we conclude that signaling via the HER2/HER3 pathway in breast carcinoma cell lines may lead to enhanced NKG2D-MICA/B recognition by NK cells and T cells. The Journal of Immunology, 2012, 188: 2136-2145.