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Blockade of the immunosuppressive KIR2DL5/PVR pathway elicits potent human NK cell–mediated antitumor immunity
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 pathwa...
Autores principales: | , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
American Society for Clinical Investigation
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9663162/ https://www.ncbi.nlm.nih.gov/pubmed/36377656 http://dx.doi.org/10.1172/JCI163620 |
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author | Ren, Xiaoxin Peng, Mou Xing, Peng Wei, Yao Galbo, Phillip M. Corrigan, Devin Wang, Hao Su, Yingzhen Dong, Xiaoshen Sun, Qizhe Li, Yixian Zhang, Xiaoyu Edelmann, Winfried Zheng, Deyou Zang, Xingxing |
author_facet | Ren, Xiaoxin Peng, Mou Xing, Peng Wei, Yao Galbo, Phillip M. Corrigan, Devin Wang, Hao Su, Yingzhen Dong, Xiaoshen Sun, Qizhe Li, Yixian Zhang, Xiaoyu Edelmann, Winfried Zheng, Deyou Zang, Xingxing |
author_sort | Ren, Xiaoxin |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-9663162 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | American Society for Clinical Investigation |
record_format | MEDLINE/PubMed |
spelling | pubmed-96631622022-11-17 Blockade of the immunosuppressive KIR2DL5/PVR pathway elicits potent human NK cell–mediated antitumor immunity Ren, Xiaoxin Peng, Mou Xing, Peng Wei, Yao Galbo, Phillip M. Corrigan, Devin Wang, Hao Su, Yingzhen Dong, Xiaoshen Sun, Qizhe Li, Yixian Zhang, Xiaoyu Edelmann, Winfried Zheng, Deyou Zang, Xingxing J Clin Invest Research Article 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. American Society for Clinical Investigation 2022-11-15 /pmc/articles/PMC9663162/ /pubmed/36377656 http://dx.doi.org/10.1172/JCI163620 Text en © 2022 Ren et al. https://creativecommons.org/licenses/by/4.0/This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . |
spellingShingle | Research Article Ren, Xiaoxin Peng, Mou Xing, Peng Wei, Yao Galbo, Phillip M. Corrigan, Devin Wang, Hao Su, Yingzhen Dong, Xiaoshen Sun, Qizhe Li, Yixian Zhang, Xiaoyu Edelmann, Winfried Zheng, Deyou Zang, Xingxing Blockade of the immunosuppressive KIR2DL5/PVR pathway elicits potent human NK cell–mediated antitumor immunity |
title | Blockade of the immunosuppressive KIR2DL5/PVR pathway elicits potent human NK cell–mediated antitumor immunity |
title_full | Blockade of the immunosuppressive KIR2DL5/PVR pathway elicits potent human NK cell–mediated antitumor immunity |
title_fullStr | Blockade of the immunosuppressive KIR2DL5/PVR pathway elicits potent human NK cell–mediated antitumor immunity |
title_full_unstemmed | Blockade of the immunosuppressive KIR2DL5/PVR pathway elicits potent human NK cell–mediated antitumor immunity |
title_short | Blockade of the immunosuppressive KIR2DL5/PVR pathway elicits potent human NK cell–mediated antitumor immunity |
title_sort | blockade of the immunosuppressive kir2dl5/pvr pathway elicits potent human nk cell–mediated antitumor immunity |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9663162/ https://www.ncbi.nlm.nih.gov/pubmed/36377656 http://dx.doi.org/10.1172/JCI163620 |
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