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PVRIG is a novel natural killer cell immune checkpoint receptor in acute myeloid leukemia
- 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.
- Subjects :
- Myeloid
Cell
Receptors, Cell Surface
Lymphocyte Activation
Article
Natural killer cell
03 medical and health sciences
0302 clinical medicine
medicine
Humans
Chemistry
Myeloid leukemia
Hematology
Immune Checkpoint Proteins
medicine.disease
Immune checkpoint
Killer Cells, Natural
Leukemia, Myeloid, Acute
Leukemia
medicine.anatomical_structure
Cell killing
Cancer research
Receptors, Natural Killer Cell
Immunotherapy
Poliovirus Receptor
030215 immunology
Subjects
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