Human leukocyte antigen-G (HLA-G) has long been speculated as a beneficial factor for a successful pregnancy for its restricted expression on fetal-maternal extravillous cytotrophoblasts and its capability of modulati...Human leukocyte antigen-G (HLA-G) has long been speculated as a beneficial factor for a successful pregnancy for its restricted expression on fetal-maternal extravillous cytotrophoblasts and its capability of modulating uterine natural killer cell (uNK) function such as cytotoxicity and cytokine production through NK cell receptors. HLA class I α1 domain is an important killer cell Ig-like receptor (KIR) recognition site and the Met76 and Gln79 are unique to HLA-G in this region. NK cell receptor KIR2DL4 is a specific receptor for HLA-G, yet the recognition site on HLA-G remains unknown. In this study, retroviral transduction was applied to express the wild type HLA-G (HLA-wtG), mutant HLA-G (HLA-mG) on the chronic myelogenous leukemia cell line K562 cells and KIR2DL4 molecule on NK-92 cells, respectively. KIR2DL4-IgG Fc fusion protein was generated to determine the binding specificity between KIR2DL4 and HLA-G. Our results showed that residue Met76, Gln79 mutated to Ala76,79 in the α1 domain of HLA-G protein could affect the binding affinity between KIR2DL4 and HLA-G, meanwhile, the KIR2DL4 transfected NK-92 cells (NK-92- 2DL4) showed a considerably different cytolysis ability against the HLA-wtG and HLA-mG transfected K562 targets. Taken together, our data indicated that residue Met76 and Gln79 in HLA-G α1 domain plays a critical role in the recogni- tion of KIR2DL4, which could be an explanation for the isoforms of HLA-G, all containing the α1 domain, with the potential to regulate NK functions.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
To better understand the pathogenesis of Sézary cells, distinguish them from reactive skin-infltrating T-cells and improve disease treatment, efforts have been made to identify molecular targets deregulated by th...To better understand the pathogenesis of Sézary cells, distinguish them from reactive skin-infltrating T-cells and improve disease treatment, efforts have been made to identify molecular targets deregulated by the malignant process. From immunophenotypic analysis and subtractive differential expression experiments to pan-genomic studies, many approaches have been used to identify markers of the disease. During the last decade several natural killer （NK） cell markers have been found aberrantly expressed at the surface of Sézary cells. In particular, KIR3DL2/CD158k, expressed by less than 2% of healthy individuals CD4＋ T-cells, is an excellent marker to identify and follow the tumor burden in the blood of Sézary syndrome patients. It may also represent a valuable target for specifc im-munotherapy. Other products of the NK cluster on chromosome 19q13 have been detected on Sézary cells, raising the hypothesis of an NK reprogramming process associated with the malignant transformation that may induce survival functions.展开更多
文摘Human leukocyte antigen-G (HLA-G) has long been speculated as a beneficial factor for a successful pregnancy for its restricted expression on fetal-maternal extravillous cytotrophoblasts and its capability of modulating uterine natural killer cell (uNK) function such as cytotoxicity and cytokine production through NK cell receptors. HLA class I α1 domain is an important killer cell Ig-like receptor (KIR) recognition site and the Met76 and Gln79 are unique to HLA-G in this region. NK cell receptor KIR2DL4 is a specific receptor for HLA-G, yet the recognition site on HLA-G remains unknown. In this study, retroviral transduction was applied to express the wild type HLA-G (HLA-wtG), mutant HLA-G (HLA-mG) on the chronic myelogenous leukemia cell line K562 cells and KIR2DL4 molecule on NK-92 cells, respectively. KIR2DL4-IgG Fc fusion protein was generated to determine the binding specificity between KIR2DL4 and HLA-G. Our results showed that residue Met76, Gln79 mutated to Ala76,79 in the α1 domain of HLA-G protein could affect the binding affinity between KIR2DL4 and HLA-G, meanwhile, the KIR2DL4 transfected NK-92 cells (NK-92- 2DL4) showed a considerably different cytolysis ability against the HLA-wtG and HLA-mG transfected K562 targets. Taken together, our data indicated that residue Met76 and Gln79 in HLA-G α1 domain plays a critical role in the recogni- tion of KIR2DL4, which could be an explanation for the isoforms of HLA-G, all containing the α1 domain, with the potential to regulate NK functions.
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.
基金the Inserm, Société de Recherches Dermatologiques (SRD C.S), and Société Franaise de Dermatologie (SFD A.M-C) for their support as well as the European Union through the Euro-Trans-Bio grant (M.B and A.B)
文摘To better understand the pathogenesis of Sézary cells, distinguish them from reactive skin-infltrating T-cells and improve disease treatment, efforts have been made to identify molecular targets deregulated by the malignant process. From immunophenotypic analysis and subtractive differential expression experiments to pan-genomic studies, many approaches have been used to identify markers of the disease. During the last decade several natural killer （NK） cell markers have been found aberrantly expressed at the surface of Sézary cells. In particular, KIR3DL2/CD158k, expressed by less than 2% of healthy individuals CD4＋ T-cells, is an excellent marker to identify and follow the tumor burden in the blood of Sézary syndrome patients. It may also represent a valuable target for specifc im-munotherapy. Other products of the NK cluster on chromosome 19q13 have been detected on Sézary cells, raising the hypothesis of an NK reprogramming process associated with the malignant transformation that may induce survival functions.
