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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-\u03b3 (IFN-\u03b3) production pathway, in which IFN-\u03b3 upregulates KIR2DL4 via JAK2\/STAT1 signaling, and then KIR2DL4 synergizes with the Fc\u03b3 receptor to increase IFN-\u03b3 secretion by NK cells. Trastuzumab treatment of neoplastic and NK cells leads to aberrant cytokine production characterized by excessive tumor growth factor-\u03b2 (TGF-\u03b2) and IFN-\u03b3, which subsequently reinforce HLA-G\/KIR2DL4 signaling. In addition, TGF-\u03b2 and IFN-\u03b3 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.<\/jats:p>","DOI":"10.1038\/s41392-021-00629-w","type":"journal-article","created":{"date-parts":[[2021,6,22]],"date-time":"2021-06-22T20:02:59Z","timestamp":1624392179000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":100,"title":["Interaction between HLA-G and NK cell receptor KIR2DL4 orchestrates HER2-positive breast cancer resistance to trastuzumab"],"prefix":"10.1038","volume":"6","author":[{"given":"Guoxu","family":"Zheng","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhangyan","family":"Guo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Weimiao","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenjin","family":"Xi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Baile","family":"Zuo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rui","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Weihong","family":"Wen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8854-4672","authenticated-orcid":false,"given":"An-Gang","family":"Yang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lintao","family":"Jia","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2021,6,23]]},"reference":[{"key":"629_CR1","doi-asserted-by":"publisher","first-page":"7350","DOI":"10.1200\/JCO.2005.03.3845","volume":"23","author":"JD Brenton","year":"2005","unstructured":"Brenton, J. 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