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PVRIG is a novel natural killer cell immune checkpoint receptor in acute myeloid leukemia
This study explored the novel immune checkpoint poliovirus receptor- related immunoglobulin domain-containing (PVRIG) in acute myeloid leukemia (AML). We showed that AML patient blasts consistently expressed the PVRIG ligand (poliovirus receptor-related 2, PVRL2). Furthermore, PVRIG blockade signifi...
Autores principales: | , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Fondazione Ferrata Storti
2020
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8634199/ https://www.ncbi.nlm.nih.gov/pubmed/33147937 http://dx.doi.org/10.3324/haematol.2020.258574 |
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author | Li, Jessica Whelan, Sarah Kotturi, Maya F. Meyran, Deborah D’Souza, Criselle Hansen, Kyle Liang, Spencer Hunter, John Trapani, Joseph A. Neeson, Paul J. |
author_facet | Li, Jessica Whelan, Sarah Kotturi, Maya F. Meyran, Deborah D’Souza, Criselle Hansen, Kyle Liang, Spencer Hunter, John Trapani, Joseph A. Neeson, Paul J. |
author_sort | Li, Jessica |
collection | PubMed |
description | This study explored the novel immune checkpoint poliovirus receptor- related immunoglobulin domain-containing (PVRIG) in acute myeloid leukemia (AML). We showed that AML patient blasts consistently expressed the PVRIG ligand (poliovirus receptor-related 2, PVRL2). Furthermore, PVRIG blockade significantly enhanced naural killer (NK)-cell killing of PVRL2+, poliovirus receptor (PVR)lo AML cell lines, and significantly increased NK-cell activation and degranulation in the context of patient primary AML blasts. However, in AML patient bone marrow, NK-cell PVRIG expression levels were not increased. In order to understand how PVRIG blockade might potentially be exploited therapeutically, we investigated the biology of PVRIG and revealed that NK-cell activation resulted in reduced PVRIG expression on the cell surface. This occurred whether NK cells were activated by tumor cell recognition, cytokines (interleukin 2 [IL-2] and IL-12) or activating receptor stimulation (CD16 and NKp46). PVRIG was present at higher levels in the cytoplasm than on the cell surface, particularly on CD56bright NK cells, which further increased cytoplasmic PVRIG levels following IL-2 and IL-12 activation. PVRIG was continually transported to the cell surface via the endoplasmic reticulum and Golgi in both unstimulated and activated NK cells. Taken together, our findings suggest that anti-PVRIG blocking antibody functions by binding to surface-bound PVRIG, which undergoes rapid turnover in both unstimulated and activated NK cells. We conclude that the PVRIG-PVRL2 immune checkpoint axis can feasibly be targeted with PVRIG blocking antibody for NK-mediated immunotherapy of PVRL2+ AML. |
format | Online Article Text |
id | pubmed-8634199 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | Fondazione Ferrata Storti |
record_format | MEDLINE/PubMed |
spelling | pubmed-86341992021-12-17 PVRIG is a novel natural killer cell immune checkpoint receptor in acute myeloid leukemia Li, Jessica Whelan, Sarah Kotturi, Maya F. Meyran, Deborah D’Souza, Criselle Hansen, Kyle Liang, Spencer Hunter, John Trapani, Joseph A. Neeson, Paul J. Haematologica Article This study explored the novel immune checkpoint poliovirus receptor- related immunoglobulin domain-containing (PVRIG) in acute myeloid leukemia (AML). We showed that AML patient blasts consistently expressed the PVRIG ligand (poliovirus receptor-related 2, PVRL2). Furthermore, PVRIG blockade significantly enhanced naural killer (NK)-cell killing of PVRL2+, poliovirus receptor (PVR)lo AML cell lines, and significantly increased NK-cell activation and degranulation in the context of patient primary AML blasts. However, in AML patient bone marrow, NK-cell PVRIG expression levels were not increased. In order to understand how PVRIG blockade might potentially be exploited therapeutically, we investigated the biology of PVRIG and revealed that NK-cell activation resulted in reduced PVRIG expression on the cell surface. This occurred whether NK cells were activated by tumor cell recognition, cytokines (interleukin 2 [IL-2] and IL-12) or activating receptor stimulation (CD16 and NKp46). PVRIG was present at higher levels in the cytoplasm than on the cell surface, particularly on CD56bright NK cells, which further increased cytoplasmic PVRIG levels following IL-2 and IL-12 activation. PVRIG was continually transported to the cell surface via the endoplasmic reticulum and Golgi in both unstimulated and activated NK cells. Taken together, our findings suggest that anti-PVRIG blocking antibody functions by binding to surface-bound PVRIG, which undergoes rapid turnover in both unstimulated and activated NK cells. We conclude that the PVRIG-PVRL2 immune checkpoint axis can feasibly be targeted with PVRIG blocking antibody for NK-mediated immunotherapy of PVRL2+ AML. Fondazione Ferrata Storti 2020-11-05 /pmc/articles/PMC8634199/ /pubmed/33147937 http://dx.doi.org/10.3324/haematol.2020.258574 Text en Copyright© 2021 Ferrata Storti Foundation https://creativecommons.org/licenses/by-nc/4.0/This article is distributed under the terms of the Creative Commons Attribution Noncommercial License (by-nc 4.0) which permits any noncommercial use, distribution, and reproduction in any medium, provided the original author(s) and source are credited. |
spellingShingle | Article Li, Jessica Whelan, Sarah Kotturi, Maya F. Meyran, Deborah D’Souza, Criselle Hansen, Kyle Liang, Spencer Hunter, John Trapani, Joseph A. Neeson, Paul J. PVRIG is a novel natural killer cell immune checkpoint receptor in acute myeloid leukemia |
title | PVRIG is a novel natural killer cell immune checkpoint receptor in acute myeloid leukemia |
title_full | PVRIG is a novel natural killer cell immune checkpoint receptor in acute myeloid leukemia |
title_fullStr | PVRIG is a novel natural killer cell immune checkpoint receptor in acute myeloid leukemia |
title_full_unstemmed | PVRIG is a novel natural killer cell immune checkpoint receptor in acute myeloid leukemia |
title_short | PVRIG is a novel natural killer cell immune checkpoint receptor in acute myeloid leukemia |
title_sort | pvrig is a novel natural killer cell immune checkpoint receptor in acute myeloid leukemia |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8634199/ https://www.ncbi.nlm.nih.gov/pubmed/33147937 http://dx.doi.org/10.3324/haematol.2020.258574 |
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