Immune checkpoints PVR and PVRL2 are prognostic markers in AML and their blockade represents a new therapeutic option

Hauke Stamm,Ulrike Mock,Carsten Bokemeyer,Eva-Maria Grossjohann,Roman Kischel,Dirk Nagorsen,Emily Latuske,Eik Vettorazzi,Walter Fiedler,Felicitas Thol,Matthias Friedrich,Michael Heuser,Jasmin Wellbrock,Cedric Dos Santos,Sabine Stienen,Jana Muschhammer,Gabi Vohwinkel,Felix Klingler,Michael Lutteropp

doi:10.1038/s41388-018-0288-y

Abstract

Immune checkpoints are promising targets in cancer therapy. Recently, poliovirus receptor (PVR) and poliovirus receptor-related 2 (PVRL2) have been identified as novel immune checkpoints. In this investigation we show that acute myeloid leukemia (AML) cell lines and AML patient samples highly express the T-cell immunoreceptor with Ig and ITIM domains (TIGIT) ligands PVR and PVRL2. Using two independent patient cohorts, we could demonstrate that high PVR and PVRL2 expression correlates with poor outcome in AML. We show for the first time that antibody blockade of PVR or PVRL2 on AML cell lines or primary AML cells or TIGIT blockade on immune cells increases the anti-leukemic effects mediated by PBMCs or purified CD3+ cells in vitro. The cytolytic activity of the BiTE® antibody construct AMG 330 against leukemic cells could be further enhanced by blockade of the TIGIT-PVR/PVRL2 axis. This increased immune reactivity is paralleled by augmented secretion of Granzyme B by immune cells. Employing CRISPR/Cas9-mediated knockout of PVR and PVRL2 in MV4-11 cells, the cytotoxic effects of antibody blockade could be recapitulated in vitro. In NSG mice reconstituted with human T cells and transplanted with either MV4-11 PVR/PVRL2 knockout or wildtype cells, prolonged survival was observed for the knockout cells. This survival benefit could be further extended by treating the mice with AMG 330. Therefore, targeting the TIGIT-PVR/PVRL2 axis with blocking antibodies might represent a promising future therapeutic option in AML.

Highlights

These authors contributed : Jasmin Wellbrock and Walter Fiedler.Electronic supplementary material The online version of this article contains supplementary material, which is available to authorized users.Escape of neoplastic cells from immune destruction has recently been added to the list of hallmarks of cancer [1]
We explored the therapeutic potential of inhibition of the novel immune regulators poliovirus receptor (PVR, CD155, Tage 4) and poliovirus receptor-related 2 (PVRL2, CD112, Nectin-2, PRR2), which bind to the CD28 family member T cell immunoreceptor with Ig and immunoreceptor tyrosinebased inhibitory motif (ITIM) domains (TIGIT)
We show that acute myeloid leukemia (AML) cell lines as well as AML cells from untreated patients express PVR and poliovirus receptorrelated 2 (PVRL2) to a high extent

Summary

Introduction

These authors contributed : Jasmin Wellbrock and Walter Fiedler. For the treatment of acute myeloid leukemia (AML), AMG 330, a CD33/CD3 BiTE® antibody construct, has shown preclinical activity and is currently undergoing phase 1 clinical testing (NCT02520427) [9, 10]. Combining both approaches, tumor cell killing by T cells in the presence of BiTE® antibody constructs, as well as blockade of checkpoint molecules may result in enhanced therapeutic efficacy

Methods

Results

Conclusion