目的研究KIR2DL3/HLA-C1基因组合与丙型肝炎病毒(Hepatitis C virus,HCV)清除的相关性。方法本研究对随机抽取的无血缘关系的40个健康成人(中国汉族)外周血样本进行了KIR及HLA-Cw基因分型,并分析了与HCV清除相关的KIR2DL3/HLA-C1基因组...目的研究KIR2DL3/HLA-C1基因组合与丙型肝炎病毒(Hepatitis C virus,HCV)清除的相关性。方法本研究对随机抽取的无血缘关系的40个健康成人(中国汉族)外周血样本进行了KIR及HLA-Cw基因分型,并分析了与HCV清除相关的KIR2DL3/HLA-C1基因组合的分布情况。结果 40例样本中HLA-Cw位点HLA-C1基因出现频率较HLA-C2高,且HLA-C1C1出现的频率较HLA-C1C2高;KIR基因型中,以3DL1、2DL1、2DL3、2DL4、3DL2、3DL3、2DP1、3DP1、2DS4出现频率较高,而3DS1、2DS1、2DS2、2DS3、2DS5、2DL2、2DL5出现频率较低;KIR2DL3+/HLA-C1C1例数较KIR2DL2+/HLA-C1C1多。综合分析发现,KIR2DL3+/HLA-C1基因型组合以KIR2DL3-2DL3/HLA-C1C1者较多,占总样本数52.5%。结论以本研究为基础,可进一步研究KIR2DL3/HLA-C1基因型组合与NK细胞体外抑制HCV活性的相关性,探讨HLA-Cw基因型为C1C1的个体中,KIR 2DL3-2DL3个体的NK细胞是否较2DL2-2DL2个体以及2DL3-2DL2个体的NK细胞具有更强的抑制HCV活性的作用,为丙型肝炎的免疫治疗及疫苗研制提供依据。展开更多
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 d...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 Fey 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.展开更多
文摘目的研究KIR2DL3/HLA-C1基因组合与丙型肝炎病毒(Hepatitis C virus,HCV)清除的相关性。方法本研究对随机抽取的无血缘关系的40个健康成人(中国汉族)外周血样本进行了KIR及HLA-Cw基因分型,并分析了与HCV清除相关的KIR2DL3/HLA-C1基因组合的分布情况。结果 40例样本中HLA-Cw位点HLA-C1基因出现频率较HLA-C2高,且HLA-C1C1出现的频率较HLA-C1C2高;KIR基因型中,以3DL1、2DL1、2DL3、2DL4、3DL2、3DL3、2DP1、3DP1、2DS4出现频率较高,而3DS1、2DS1、2DS2、2DS3、2DS5、2DL2、2DL5出现频率较低;KIR2DL3+/HLA-C1C1例数较KIR2DL2+/HLA-C1C1多。综合分析发现,KIR2DL3+/HLA-C1基因型组合以KIR2DL3-2DL3/HLA-C1C1者较多,占总样本数52.5%。结论以本研究为基础,可进一步研究KIR2DL3/HLA-C1基因型组合与NK细胞体外抑制HCV活性的相关性,探讨HLA-Cw基因型为C1C1的个体中,KIR 2DL3-2DL3个体的NK细胞是否较2DL2-2DL2个体以及2DL3-2DL2个体的NK细胞具有更强的抑制HCV活性的作用,为丙型肝炎的免疫治疗及疫苗研制提供依据。
基金This work was supported by the National Natural Sciences Foundation of China(Nos.81630069,81872326,and 81872303)the Natural Science Research and Development Program of Shaanxi Province(2018SF-215 and 2020SF-115)the Fundamental Research Funds for the Central Universities(szy012019083).
文摘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 Fey 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.
