ArticleSignal transduction and targeted therapy2021
Interaction between HLA-G and NK cell receptor KIR2DL4 orchestrates HER2-positive breast cancer resistance to trastuzumab.
Article in Signal transduction and targeted therapy, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 73 papers.
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Who cites it
73 citing papers in PubMed, 101 citations in OpenAlex.
- Multi-payload antibody-drug conjugates for photothermal dynamic and chemotherapy of HER2-positive breast cancer.Materials today. Bio · 2026Article
- SPP1-positive macrophages drive trastuzumab resistance in HER2-positive breast cancer.Cell communication and signaling : CCS · 2026Article
- Targeting the CCL5/CCR5-PI3K-AKT axis suppresses hepatic stellate cell-induced breast cancer metastasis.Cancer cell international · 2026Article
- JAK/STAT-mediated regulation of PD-L1 expression in breast cancer: Molecular mechanisms and implications for immunotherapy.iScience · 2026Review
- Human pluripotent stem cell-derived innate and adaptive immune cells for cancer immunotherapy.Cell stem cell · 2026Review
- The non-classical immune checkpoint HLA-G: a regulatory master switch governing tolerance, evasion, and translational frontiers.Frontiers in oncology · 2026Review
- Development and evaluation of an inhalable nanoemulsion system for enhancing NK cell function against osteosarcoma pulmonary metastases.Frontiers in immunology · 2026Article
- Molecular innate immune programs of tumor-associated macrophages in immune checkpoint blockade resistance: a staged framework from suppressive circuitry to translational bottlenecks.Frontiers in immunology · 2026Review
- Human leukocyte antigen-G in solid tumors: from immunotolerance to immunotherapy.Frontiers in immunology · 2026Review
- Understanding the immunomodulatory mechanisms for natural products that overcome tumor chemoresistance to platinum-based cancer drugs and other treatments.Frontiers in pharmacology · 2026Review
- Targeting the tripartite axis of immune-metabolic-spatial crosstalk to overcome therapy resistance in breast cancer.Frontiers in immunology · 2026Review
- Research Advances in Drug Resistance Mechanisms to Anti-HER2 Therapy in HER2-Positive Breast Cancer.Oncology research · 2026Review
- TAK-981 potentiates doxorubicin immunocide in triple-negative breast cancer by IFN I-dependent NK cell stimulation.Cellular oncology (Dordrecht, Netherlands) · 2025Article
- Prognostic and predictive significance of neutrophil/lymphocyte ratio for trastuzumab treatment efficacy in HER2-positive breast cancer.Scientific reports · 2025Article
- Targeting of the CD161 Inhibitory Receptor Enhances Bone-Marrow-Resident Memory CD8Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2025Article
- Emerging roles of KIR2DL4 in cancer immunotherapy.Breast cancer (Tokyo, Japan) · 2025Review
- Bioinformatic Analysis of the Significance of the KIR2DL4 Gene in Recurrent Implantation Failure.Biochemical genetics · 2025Article
- T-cell activation enhances anti-HER2-mediated antibody-dependent cellular cytotoxicity in gastric cancer.Immunologic research · 2025Article
- Mechanism of microRNA-152 Regulating Decidual Natural Killer Cell Viability and Affecting Trophoblast Cell Invasiveness via the HLA-G/KIR2DL4 Axis.The Kaohsiung journal of medical sciences · 2025Article
- New approaches of chimeric antigen receptor (CAR)-immune cell-based therapy in gastric cancer; highlight CAR-T and CAR-NK.Functional & integrative genomics · 2025Review
13 more citing papers are in PubMed but not listed here.
Corrections and comments
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Authors and funding
9 authors at 2 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
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 then KIR2DL4 synergizes with the Fcγ 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.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.