دورية أكاديمية
Interaction between HLA-G and NK cell receptor KIR2DL4 orchestrates HER2-positive breast cancer resistance to trastuzumab
العنوان: | Interaction between HLA-G and NK cell receptor KIR2DL4 orchestrates HER2-positive breast cancer resistance to trastuzumab |
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المؤلفون: | Guoxu Zheng, Zhangyan Guo, Weimiao Li, Wenjin Xi, Baile Zuo, Rui Zhang, Weihong Wen, An-Gang Yang, Lintao Jia |
المصدر: | Signal Transduction and Targeted Therapy, Vol 6, Iss 1, Pp 1-15 (2021) |
بيانات النشر: | Nature Publishing Group, 2021. |
سنة النشر: | 2021 |
المجموعة: | LCC:Medicine LCC:Biology (General) |
مصطلحات موضوعية: | Medicine, Biology (General), QH301-705.5 |
الوصف: | Abstract Despite the successful use of the humanized monoclonal antibody trastuzumab (Herceptin) in the clinical treatment of human epidermal growth factor receptor 2 (HER2)-overexpressing breast cancer, the frequently occurring drug resistance remains to be overcome. The regulatory mechanisms of trastuzumab-elicited immune response in the tumor microenvironment remain largely uncharacterized. Here, we found that the nonclassical histocompatibility antigen HLA-G desensitizes breast cancer cells to trastuzumab by binding to the natural killer (NK) cell receptor KIR2DL4. Unless engaged by HLA-G, KIR2DL4 promotes antibody-dependent cell-mediated cytotoxicity and forms a regulatory circuit with the interferon-γ (IFN-γ) production pathway, in which IFN-γ upregulates KIR2DL4 via JAK2/STAT1 signaling, and then KIR2DL4 synergizes with the Fcγ receptor to increase IFN-γ secretion by NK cells. Trastuzumab treatment of neoplastic and NK cells leads to aberrant cytokine production characterized by excessive tumor growth factor-β (TGF-β) and IFN-γ, which subsequently reinforce HLA-G/KIR2DL4 signaling. In addition, TGF-β and IFN-γ impair the cytotoxicity of NK cells by upregulating PD-L1 on tumor cells and PD-1 on NK cells. Blockade of HLA-G/KIR2DL4 signaling improved the vulnerability of HER2-positive breast cancer to trastuzumab treatment in vivo. These findings provide novel insights into the mechanisms underlying trastuzumab resistance and demonstrate the applicability of combined HLA-G and PD-L1/PD-1 targeting in the treatment of trastuzumab-resistant breast cancer. |
نوع الوثيقة: | article |
وصف الملف: | electronic resource |
اللغة: | English |
تدمد: | 2059-3635 |
Relation: | https://doaj.org/toc/2059-3635 |
DOI: | 10.1038/s41392-021-00629-w |
URL الوصول: | https://doaj.org/article/26fd9ddfa6ea4c7faf5f429c10d12cd1 |
رقم الأكسشن: | edsdoj.26fd9ddfa6ea4c7faf5f429c10d12cd1 |
قاعدة البيانات: | Directory of Open Access Journals |
تدمد: | 20593635 |
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DOI: | 10.1038/s41392-021-00629-w |