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Citations to this article

Blockade of the immunosuppressive KIR2DL5/PVR pathway elicits potent human NK cell–mediated antitumor immunity
Xiaoxin Ren, … , Deyou Zheng, Xingxing Zang
Xiaoxin Ren, … , Deyou Zheng, Xingxing Zang
Published November 15, 2022
Citation Information: J Clin Invest. 2022;132(22):e163620. https://doi.org/10.1172/JCI163620.
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Research Article Immunology Oncology Article has an altmetric score of 502

Blockade of the immunosuppressive KIR2DL5/PVR pathway elicits potent human NK cell–mediated antitumor immunity

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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.

Authors

Xiaoxin Ren, Mou Peng, Peng Xing, Yao Wei, Phillip M. Galbo Jr., Devin Corrigan, Hao Wang, Yingzhen Su, Xiaoshen Dong, Qizhe Sun, Yixian Li, Xiaoyu Zhang, Winfried Edelmann, Deyou Zheng, Xingxing Zang

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Total citations by year

Year: 2025 2024 2023 Total
Citations: 5 9 9 23
Citation information
This citation data is accumulated from CrossRef, which receives citation information from participating publishers, including this journal. Not all publishers participate in CrossRef, so this information is not comprehensive. Additionally, data may not reflect the most current citations to this article, and the data may differ from citation information available from other sources (for example, Google Scholar, Web of Science, and Scopus).

Citations to this article in year 2023 (9)

Title and authors Publication Year
Targets of Immune Escape Mechanisms in Cancer: Basis for Development and Evolution of Cancer Immune Checkpoint Inhibitors
Dutta S, Ganguly A, Chatterjee K, Spada S, Mukherjee S
Biology 2023
GPR116 receptor regulates the antitumor function of NK cells via Gαq/HIF1α/NF-κB signaling pathway as a potential immune checkpoint.
Guo D, Jin C, Gao Y, Lin H, Zhang L, Zhou Y, Yao J, Duan Y, Ren Y, Hui X, Ge Y, Yang R, Jiang W
Cell & Bioscience 2023
TIGIT Expression on Activated NK Cells Correlates with Greater Anti-Tumor Activity but Promotes Functional Decline upon Lung Cancer Exposure: Implications for Adoptive Cell Therapy and TIGIT-Targeted Therapies
Hasan MF, Croom-Perez TJ, Oyer JL, Dieffenthaller TA, Robles-Carrillo LD, Eloriaga JE, Kumar S, Andersen BW, Copik AJ
Cancers 2023
Reactivation of natural killer cells with monoclonal antibodies in the microenvironment of malignant neoplasms.
Soldi LR, Silva VLC, Rabelo DH, Uehara IA, Silva MJB
Journal of Cancer Research and Clinical Oncology 2023
Killer cell immunoglobulin-like receptor (KIR) genes and their HLA ligands in a Brazilian population
Cardozo DM, Marangon AV, Guimarães F, Marques S, Lieber S, Delamain M, Aranha F, Visentainer JE, de Souza CA
Innate immunity 2023
Dysregulation of DNAM-1-Mediated NK Cell Anti-Cancer Responses in the Tumor Microenvironment
Paolini R, Molfetta R
Cancers 2023
Killer instincts: natural killer cells as multifactorial cancer immunotherapy
Nersesian S, Carter EB, Lee SN, Westhaver LP, Boudreau JE
Frontiers in immunology 2023
The KIR repertoire of a West African chimpanzee population is characterized by limited gene, allele, and haplotype variation
de Groot NG, Heijmans CM, van der Wiel MK, Bruijnesteijn J, Bontrop RE
Frontiers in immunology 2023
Ovarian cancer treatment and natural killer cell-based immunotherapy
Fan Z, Han D, Fan X, Zhao L
Frontiers in immunology 2023

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