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

TY - JOUR

T1 - Immune checkpoints PVR and PVRL2 are prognostic markers in AML and their blockade represents a new therapeutic option

AU - Stamm, Hauke

AU - Klingler, Felix

AU - Grossjohann, Eva-Maria

AU - Muschhammer, Jana

AU - Vettorazzi, Eik

AU - Heuser, Michael

AU - Mock, Ulrike

AU - Thol, Felicitas

AU - Vohwinkel, Gabi

AU - Latuske, Emily

AU - Bokemeyer, Carsten

AU - Kischel, Roman

AU - Dos Santos, Cedric

AU - Stienen, Sabine

AU - Friedrich, Matthias

AU - Lutteropp, Michael

AU - Nagorsen, Dirk

AU - Wellbrock, Jasmin

AU - Fiedler, Walter

PY - 2018/9

Y1 - 2018/9

N2 - 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.

AB - 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.

KW - Journal Article

U2 - 10.1038/s41388-018-0288-y

DO - 10.1038/s41388-018-0288-y

M3 - SCORING: Journal article

C2 - 29855615

VL - 37

SP - 5269

EP - 5280

JO - ONCOGENE

JF - ONCOGENE

SN - 0950-9232

IS - 39

ER -