Interaction between HLA-G and NK cell receptor KIR2DL4 orchestrates HER2-positive breast cancer resistance to trastuzumab

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.