Targeting cell-surface VISTA expression on allospecific naïve T cells promotes tolerance
Abstract
Abstract The success of allogeneic hematopoietic stem cell transplantation (allo-HSCT) can be limited by graft-versus-host disease (GVHD). T-cell activation is a key factor in GVHD progression. Costimulatory signals can be counterbalanced by coinhibitory signals such as the checkpoint molecule VISTA (V-domain immunoglobulin-containing suppressor of T-cell activation)/programmed death-1 homolog that restrains activation and maintains donor T-cell quiescence. A single dose of anti-VISTA monoclonal antibody (mAb) prevents acute GVHD lethality in multiple models. Naïve donor T cells express moderate VISTA levels, which transiently increase in allo-HSCT recipients in association with T-cell receptor signaling, leading to heightened susceptibility to anti-VISTA mAb–mediated depletion, in contrast to donor T cells transferred to syngeneic recipients. Anti-VISTA mAb donor T-cell depletion was compatible with rapamycin but incompatible with peritransplant tacrolimus GVHD prophylaxis. Targeting VISTA exclusively on host cells or donor CD8+ T cells was not protective against GVHD lethality. Instead, anti-VISTA mAb–mediated deletion of alloreactive donor T cells depended on targeting a third (non-T) cell type. Further mechanistic studies indicated that donor T cells concurrently exposed to anti-VISTA mAb in vivo but not preincubated in vitro before adoptive T-cell transfer were eliminated via Fc receptor (FcR)-mediated phagocytosis. In a lymphoma challenge model, a graft-versus-lymphoma (GVL) effect was fully retained when anti-human VISTA mAb exclusively targeted donor CD4+ T cells, and was delayed but mostly retained when unseparated donor T cells were infused. In a xenogeneic GVHD model, anti-human VISTA mAb reduced donor T-cell expansion, VISTA T-cell expression levels, and recipient lethality. Together, these data support a novel clinical translational pathway in which acute GVHD lethality can be mitigated without negating the GVL effect.
Article Details
Authors (22)
Brent H. Koehn
1Division of Pediatric Blood and Marrow Transplantation & Cellular Therapy, Department of Pediatrics, Masonic Cancer Center, University of Minnesota, Minneapolis, MN
Elizabeth C. Nowak
2Department of Microbiology and Immunology, Dartmouth Cancer Center, Geisel School of Medicine at Dartmouth, Lebanon, NH
Sladjana Skopelja-Gardner
Asim Saha
1University of Minnesota, Division of Blood and Marrow Transplantation, Department of Pediatrics, Minneapolis, United States
Michael C. Zaiken
1Division of Pediatric Blood and Marrow Transplantation & Cellular Therapy, Department of Pediatrics, Masonic Cancer Center, University of Minnesota, Minneapolis, MN
Jeremy Allred
1University of Minnesota, Division of Hematology, Oncology and Transplantation, Minneapolis, United States
Yiyung Peng
1Division of Blood and Marrow Transplantation, Department of Pediatrics, University of Minnesota Cancer Center, Minneapolis, MN
Wilson L. Davis
2Department of Microbiology and Immunology, Dartmouth Cancer Center, Geisel School of Medicine at Dartmouth, Lebanon, NH
Isabelle Le Mercier
4AvenCell Therapeutics Inc, Watertown, MA
Nicholas Schwertner
5Lifordi Immunotherapeutics, Burlington, MA
Michael J. Molloy
6ImmuNext Inc, Alton, NH
Jay Rothstein
4AvenCell Therapeutics Inc, Watertown, MA
Catherine Carriere
4AvenCell Therapeutics Inc, Watertown, MA
Megan J. Riddle
1Division of Pediatric Blood and Marrow Transplantation, Department of Pediatrics, University of Minnesota Cancer Center, Minneapolis, MN
Cindy R. Eide
1Division of Pediatric Blood and Marrow Transplantation & Cellular Therapy, Department of Pediatrics, Masonic Cancer Center, University of Minnesota, Minneapolis, MN
Jakub Tolar
1Division of Pediatric Blood and Marrow Transplantation, Department of Pediatrics, University of Minnesota Cancer Center, Minneapolis, MN
Angela Panoskaltsis-Mortari
Kyle D. Smith
1Division of Blood and Marrow Transplantation, Department of Pediatrics, University of Minnesota Cancer Center, Minneapolis, MN
Keli L. Hippen
1Division of Pediatric Blood and Marrow Transplantation, Department of Pediatrics, University of Minnesota Cancer Center, Minneapolis, MN
Tae Kon Kim
1Vanderbilt University Medical Center, Division of Hematology/Oncology, Department of Medicine, Nashville, United States
Randolph J. Noelle
2Department of Microbiology and Immunology, Dartmouth Cancer Center, Geisel School of Medicine at Dartmouth, Lebanon, NH
Bruce R. Blazar
Department of Pediatrics, Division of Blood & Marrow Transplant & Cellular Therapy, University of Minnesota