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

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

SUBMITTER: Zheng G 

PROVIDER: S-EPMC8219715 | biostudies-literature | 2021 Jun

REPOSITORIES: biostudies-literature