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

Zheng, Guoxu; Z, Guo; Li, Weimiao; Xi, Wenjin; Zuo, Baile; Zhang, Rui; Wen, Weihong; Yang, An‐Gang; Jia, Lintao

doi:10.1038/s41392-021-00629-w

Cited by 62 publications

(42 citation statements)

References 47 publications

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“…Unless engaged by HLA-G, KIR2DL4 promotes ADCC and forms a regulatory circuit with the IFN-g production pathway, in which IFN-g upregulates KIR2DL4 via JAK2/STAT1 signaling, and then KIR2DL4 synergizes with the Fcg receptor to increase IFN-g secretion by NK cells. The effect of blocking the HLA-G/KIR2DL4 interaction improves the vulnerability of HER2-positive BC to trastuzumab treatment in vivo [35].…”

Section: Blocking Inhibitory Signals Of Nk Cellsmentioning

confidence: 99%

Targeting ADCC: A different approach to HER2 breast cancer in the immunotherapy era

et al. 2021

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The clinical outcome of patients with human epidermal growth factor receptor 2 (HER2) amplified breast carcinoma (BC) has improved with the development of anti-HER2 targeted therapies. However, patients can experience disease recurrence after curative intent and disease progression in the metastatic setting. In the current era of evolving immunotherapy agents, the understanding of the immune response against HER2 tumor cells developed by anti-HER2 antibodies (Abs) is rapidly evolving. Trastuzumab therapy promotes Natural Killer (NK) cell activation in patients with BC overexpressing HER2, indicating that the efficacy of short-term trastuzumab monotherapy, albeit direct inhibition of HER, could also be related with antibody-dependent cell-mediated cytotoxicity (ADCC). Currently, dual HER2 blockade using trastuzumab and pertuzumab is the standard of care in early and advanced disease as this combination could confer an additive effect in ADCC. In patients with disease relapse or progression, ADCC may be hampered by several factors such as FcγRIIIa polymorphism and an immunosuppressive environment, among others. Hence, new drug development strategies are being investigated aiming to boost the ADCC response triggered by anti-HER2 therapy. In this review, we summarize these strategies and the rationale, through mAbs engineering and combinatorial strategies, focusing on clinical results and ongoing trials.

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Section: Blocking Inhibitory Signals Of Nk Cellsmentioning

confidence: 99%

Targeting ADCC: A different approach to HER2 breast cancer in the immunotherapy era

et al. 2021

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“…Our recent study found that KIR2DL4 synergizes with FcRg to enhance NK cell activation and degranulation, while HLA-G binding to KIR2DL4 impairs the cytotoxicity of NK cells in HER2 positive breast cancer microenvironment (7). These findings suggested that KIR2DL4 might provide a switch for NK cell activity via its association with HLA-G. Increasing evidence has showed that HLA-G is involved in both innate and adaptive immune responses required for immune escape.…”

Section: Introductionmentioning

confidence: 92%

“…Killer cell immunoglobulin-like receptor 2DL4 (KIR2DL4) is the only KIR receptor recognized by HLA-G. KIR2DL4 belongs to the killer cell Ig-like receptors (KIR) family, which is expressed mainly on NK cells (7). KIRs can recognize both classical and nonclassical HLA Class I molecules.…”

Section: Molecular Structure Of Hla-g and Kir2dl4mentioning

confidence: 99%

“…Our recent study has showed that HLA-G can desensitize breast cancer cells to trastuzumab by binding to the NK cell receptor KIR2DL4. Unless engaged by HLA-G, KIR2DL4 promotes ADCC function and forms a regulatory circuit with the IFN-g production pathway, in which IFN-g upregulates KIR2DL4 via JAK2/STAT1 signaling, and then KIR2DL4 synergizes with the CD16 to increase IFN-g secretion by NK cells (7). Recent studies have showed that the IFN-g production can impair the function of immune cells by upregulating PD-L1 on tumor cells (23)(24)(25).…”

Section: Molecular Structure Of Hla-g and Kir2dl4mentioning

confidence: 99%

“…Monoclonal antibodies against PD-1/PD-L1 and CTLA-4 have now entered clinical trials for the clinical treatment of triple negative breast cancer (6). Our recent study has showed that human leukocyte antigen-G (HLA-G) was a pivotal mediator of HER2 positive breast cancer resistance to trastuzumab and blockade of HLA-G can improve the antitumor activity of NK cells significantly (7).…”

Section: Introductionmentioning

confidence: 99%

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Roles of HLA-G/KIR2DL4 in Breast Cancer Immune Microenvironment

2022

Self Cite

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Human leukocyte antigen (HLA)-G is a nonclassical MHC Class I molecule, which was initially reported as a mediator of immune tolerance when expressed in extravillous trophoblast cells at the maternal-fetal interface. HLA-G is the only known ligand of killer cell immunoglobulin-like receptor 2DL4 (KIR2DL4), an atypical family molecule that is widely expressed on the surface of NK cells. Unlike other KIR receptors, KIR2DL4 contains both an arginine–tyrosine activation motif in its transmembrane region and an immunoreceptor tyrosine-based inhibitory motif (ITIM) in its cytoplasmic tail, suggesting that KIR2DL4 may function as an activating or inhibitory receptor. The immunosuppressive microenvironment exemplified by a rewired cytokine network and upregulated immune checkpoint proteins is a hallmark of advanced and therapy-refractory tumors. Accumulating evidence has shown that HLA-G is an immune checkpoint molecule with specific relevance in cancer immune escape, although the role of HLA-G/KIR2DL4 in antitumor immunity is still uncharacterized. Our previous study had shown that HLA-G was a pivotal mediator of breast cancer resistance to trastuzumab, and blockade of the HLA-G/KIR2DL4 interaction can resensitize breast cancer to trastuzumab treatment. In this review, we aim to summarize and discuss the role of HLA-G/KIR2DL4 in the immune microenvironment of breast cancer. A better understanding of HLA-G is beneficial to identifying novel biomarker(s) for breast cancer, which is important for precision diagnosis and prognostic assessment. In addition, it is also necessary to unravel the mechanisms underlying HLA-G/KIR2DL4 regulation of the immune microenvironment in breast cancer, hopefully providing a rationale for combined HLA-G and immune checkpoints targeting for the effective treatment of breast cancer.

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Breast Cancer Immune Landscape: Interplay Between Systemic and Local Immunity

Gerashchenko,

Frolova,

Patysheva

et al. 2024

Advanced Biology

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Breast cancer (BC) is one of the most common malignancies in women worldwide. Numerous studies in immuno‐oncology and successful trials of immunotherapy have demonstrated the causal role of the immune system in cancer pathogenesis. The interaction between the tumor and the immune system is known to have a dual nature. Despite cytotoxic lymphocyte activity against transformed cells, a tumor can escape immune surveillance and leverage chronic inflammation to maintain its own development. Research on antitumor immunity primarily focuses on the role of the tumor microenvironment, whereas the systemic immune response beyond the tumor site is described less thoroughly. Here, a comprehensive review of the formation of the immune profile in breast cancer patients is offered. The interplay between systemic and local immune reactions as self‐sustaining mechanism of tumor progression is described and the functional activity of the main cell populations related to innate and adaptive immunity is discussed. Additionally, the interaction between different functional levels of the immune system and their contribution to the development of the pro‐ or anti‐tumor immune response in BC is highlighted. The presented data can potentially inform the development of new immunotherapy strategies in the treatment of patients with BC.

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

Cited by 62 publications

References 47 publications

Targeting ADCC: A different approach to HER2 breast cancer in the immunotherapy era

Targeting ADCC: A different approach to HER2 breast cancer in the immunotherapy era

Roles of HLA-G/KIR2DL4 in Breast Cancer Immune Microenvironment

Breast Cancer Immune Landscape: Interplay Between Systemic and Local Immunity

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