ArticleThe Journal of clinical investigation2022
Blockade of the immunosuppressive KIR2DL5/PVR pathway elicits potent human NK cell-mediated antitumor immunity.
Article in The Journal of clinical investigation, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 37 papers.
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Who cites it
37 citing papers in PubMed, 53 citations in OpenAlex.
- Mechanisms of tumor cell evasion from NK cell-mediated killing and advances in NK cell-based cancer immunotherapy.Pharmaceutical science advances · 2026Review
- Gastric cancer tertiary lymphoid structures in the muscularis propria are associated with therapy resistance and promote immunosuppression.Nature communications · 2026Article
- Calcium Overloading-Induced UBE2O Upregulation Alleviates Neuronal Apoptosis.Molecular neurobiology · 2026Article
- A multi-omics dissection of INHBAJournal of translational medicine · 2026Article
- NCAPD2 Modulates MHC-I Antigen Presentation via the PI3K/AKT Axis to Drive Metastatic Progression in Gastric Cancer.Digestive diseases and sciences · 2026Article
- Integrative Roles of NK Receptors and γδ TCRs in γδ T Cell-Mediated Cancer Immunity.Immune network · 2026Review
- Dynamics of checkpoint receptors in γδ T cell subsets are associated with clinical response during anti-PD-1 immunotherapies.EMBO molecular medicine · 2026Article
- Immune system, inflammatory response, and regulated cell death in breast cancer research (Review).Oncology reports · 2026Review
- Beyond KIR and NKG2A blockade: reprogramming NK-cell immunity in solid tumors.Frontiers in cell and developmental biology · 2026Review
- Leveraging the heterogeneity of the NK cell repertoire for the development of immunotherapies for acute leukemia.Journal of translational medicine · 2025Review
- Guanine Nucleotide Exchange Factors and Small GTPases: Their Regulation and Functions, Diseases, and Therapeutic Targets.MedComm · 2025Review
- The alleviating effect of Bai-Ju essence on atopic dermatitis through anti-inflammatory and skin barrier repair mechanisms.Molecular and cellular biochemistry · 2025Article
- Emerging roles of KIR2DL4 in cancer immunotherapy.Breast cancer (Tokyo, Japan) · 2025Review
- Immunological synapse: structures, molecular mechanisms and therapeutic implications in disease.Signal transduction and targeted therapy · 2025Review
- Acquired resistance in cancer: towards targeted therapeutic strategies.Nature reviews. Cancer · 2025Review
- Molecular Interactions Between NK Cells and Acute Leukemic Cells: KIR2DL5 Drastically Limits NK Cell Responses.Journal of clinical immunology · 2025Article
- Pan-cancer analysis identifies CD155 as a promising target for CAR-T cell therapy.Genome medicine · 2025Article
- Expression of the TIGIT axis and the CD39/CD73 purinergic pathway in bone metastasis-derived immune cells.Cancer immunology, immunotherapy : CII · 2025Article
- Natural Killer Cell Immune Checkpoints and Their Therapeutic Targeting in Cancer Treatment.Research (Washington, D.C.) · 2025Article
- Interplay of KIR2DL5, nitric oxide, and tobacco smoking in predisposition to bladder cancer.Frontiers in cell and developmental biology · 2025Article
Corrections and comments
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Authors and funding
15 authors at 3 institutions in 2 countries.
Funding
Abstract
Cancer immunotherapy targeting the TIGIT/PVR pathway is currently facing challenges. KIR2DL5, a member of the human killer cell, immunoglobulin-like receptor (KIR) family, has recently been identified as another binding partner for PVR. The biology and therapeutic potential of the KIR2DL5/PVR pathway are largely unknown. Here we report that KIR2DL5 was predominantly expressed on human NK cells with mature phenotype and cytolytic function and that it bound to PVR without competition with the other 3 known PVR receptors. The interaction between KIR2DL5 on NK cells and PVR on target cells induced inhibitory synapse formation, whereas new monoclonal antibodies blocking the KIR2DL5-PVR interaction robustly augmented the NK cytotoxicity against PVR+ human tumors. Mechanistically, both intracellular ITIM and ITSM of KIR2DL5 underwent tyrosine phosphorylation after engagement, which was essential for KIR2DL5-mediated NK suppression by recruiting SHP-1 and/or SHP-2. Subsequently, ITIM/SHP-1/SHP-2 and ITSM/SHP-1 downregulated the downstream Vav1/ERK1/2/p90RSK/NF-κB signaling. KIR2DL5+ immune cells infiltrated in various types of PVR+ human cancers. Markedly, the KIR2DL5 blockade reduced tumor growth and improved overall survival across multiple NK cell-based humanized tumor models. Thus, our results revealed functional mechanisms of KIR2DL5-mediated NK cell immune evasion, demonstrated blockade of the KIR2DL5/PVR axis as a therapy for human cancers, and provided an underlying mechanism for the clinical failure of anti-TIGIT therapies.
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Registered trials
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.