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PVRIG is a novel natural killer cell immune checkpoint receptor in acute myeloid leukemia

Authors :
Joseph A. Trapani
Spencer Liang
Deborah Meyran
Maya F. Kotturi
Jessica Li
Kyle Hansen
Paul J Neeson
Sarah Whelan
John J. Hunter
Criselle D'Souza
Source :
Haematologica
Publication Year :
2020
Publisher :
Ferrata Storti Foundation (Haematologica), 2020.

Abstract

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.

Details

ISSN :
15928721 and 03906078
Volume :
106
Database :
OpenAIRE
Journal :
Haematologica
Accession number :
edsair.doi.dedup.....c3ff40a762e6e6341519d10530821042
Full Text :
https://doi.org/10.3324/haematol.2020.258574