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Cell Therapy & Immunotherapy
PVRIG is a novel natural killer cell immune checkpoint receptor in acute myeloid leukemia
Jessica Li,1,2 Sarah Whelan,3 Maya F. Kotturi,3 Deborah Meyran,1,2,4 Criselle D’Souza,1,2 Kyle Hansen,3 Spencer Liang,3 John Hunter,3 Joseph A. Trapani1,2# and Paul J. Neeson1,2#
1Cancer Immunology Program, Peter MacCallum Cancer Center Melbourne, Victoria, Australia; 12Sir Peter MacCallum Department of Oncology, The University of Melbourne, Melbourne, Victoria, Australia; 3Compugen, USA, Inc., South San Francisco, CA, USA and 4Université de Paris, INSERM, U976 HIPI Unit, Institut de Recherche Saint-Louis, Paris, France
#JAT and PJN contributed equally as co-senior authors.
ABSTRACT
This study explored the novel immune checkpoint poliovirus recep- tor-related immunoglobulin domain-containing (PVRIG) in acute myeloid leukemia (AML). We showed that AML patient blasts con- sistently 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 under- stand 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 unstim- ulated 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.
Introduction
Poliovirus receptor-related immunoglobulin domain-containing (PVRIG) has recently been identified as an immune checkpoint molecule with potential for ther- apeutic development.1 In humans, PVRIG is expressed on T cells (predominantly CD8+ T cells) and natural killer (NK) cells, but not on B cells, monocytes or neu- trophils.1 PVRIG binds to a single ligand, poliovirus receptor-related 2 (PVRL2, also known as CD112 or Nectin-2), and exerts an inhibitory effect on cytotoxic lym- phocyte activity, likely via an ITIM-like motif in its intracellular domain.1-3 PVRL2 is an adhesion molecule involved in the formation of cell-cell junctions, and is over- expressed in various cancers.4-8 PVRL2 is also a ligand of the co-activating receptor DNAX accessory molecule 1 (DNAM-1)9,10 and weakly binds another inhibitory receptor, T- cell immunoreceptor with Ig and ITIM domains (TIGIT).11-13 Recently, Whelan et al. demonstrated the inhibitory effect of PVRL2 was predominantly mediated by PVRIG and not TIGIT.3 DNAM-1 and TIGIT (but not PVRIG) also bind to a closely related molecule, poliovirus receptor (PVR, also known as CD155 or Necl-5).9,11,12 Competition studies have determined that PVR has higher affinity for TIGIT than DNAM-1, and PVRL2 has a higher affinity for PVRIG than DNAM-
Ferrata Storti Foundation
Haematologica 2021 Volume 106(12):3115-3124
Correspondence:
PAUL NEESON
paul.neeson@petermac.org
Received: May 19, 2020. Accepted: October 12, 2020. Pre-published: November 5, 2020.
https://doi.org/10.3324/haematol.2020.258574 ©2021 Ferrata Storti Foundation
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