Inflammasome-resistant IPSC-derived myeloid-derived suppressor cells ameliorate xenogeneic graft-versus-host disease
Abstract
Abstract Front-line pharmaceutical interventions for treating acute graft-versus-host disease (GVHD) are not uniformly effective and have toxic side effects. Myeloid-derived suppressor cells (MDSCs) are a heterogeneous population of immature myeloid cells with potent in vitro and in vivo immunosuppressive functions. Clinical translation of in vitro–generated MDSCs has been limited because of requirements for multiple, high infusion doses, the relatively low yield from peripheral blood–sourced MDSCs (PB-MDSCs), and inconsistent product quality. To circumvent these obstacles, we developed a methodology to generate MDSCs using human induced pluripotent stem cell (iPSC)–derived CD34+ cells. Compared with PB-MDSCs, iPSC-derived MDSCs (iMDSCs) shared similar morphology, phenotype, and suppressive function. We found that the CD14+ iMDSC subset possessed the highest suppressor function. In previous studies, we reported that MDSCs transferred into mice with GVHD lost suppressor function because of inflammasome activation and immature myeloid cell maturation. In striking contrast to human PB-MDSCs, we show herein that iMDSCs retained 95% of suppressor function in vitro despite exposure to lipopolysaccharide (LPS) plus adenosine triphosphate (ATP), which are stimuli that activate the inflammasome via danger-associated molecular patterns released during early posttransplant conditioning and GVHD-induced injury. In an in vivo xenogenic GVHD model with PB mononuclear cells, iMDSCs significantly increased recipient survival without loss of antileukemia effects. iMDSC RNA sequencing and gene knockdown studies revealed that the maintenance of the purine metabolizing enzyme, phosphoglycerate dehydrogenase, during LPS plus ATP treatment, was linked to iMDSC inflammasome resistance. Taken together, these findings provide a platform for translating in vitro–generated, off-the-shelf iMDSCs into the clinic for suppressing a spectrum of adverse immune responses, including GVHD.
Article Details
Authors (29)
Lie Ma
1Division of Pediatric Blood and Marrow Transplantation, Department of Pediatrics, University of Minnesota Cancer Center, Minneapolis, MN
Brent Koehn
1Division of Pediatric Blood and Marrow Transplantation, Department of Pediatrics, University of Minnesota Cancer Center, Minneapolis, MN
Michael Zaiken
1Division of Pediatric 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
Kyle Smith
Florida State University, Tallahassee, Florida, United States
Jeremy Allred
1University of Minnesota, Division of Hematology, Oncology and Transplantation, Minneapolis, United States
Robin Williams
1University of Minnesota, Pediatric Hematology/Oncology, Minneapolis, United States
Ke Yao
Jordan Fink
1Division of Pediatric Blood and Marrow Transplantation, Department of Pediatrics, University of Minnesota Cancer Center, Minneapolis, MN
Asim Saha
1University of Minnesota, Division of Blood and Marrow Transplantation, Department of Pediatrics, Minneapolis, United States
Benjamin Koop
1Division of Pediatric Blood and Marrow Transplantation, Department of Pediatrics, University of Minnesota Cancer Center, Minneapolis, MN
Nathaniel Payne
1Division of Pediatric Blood and Marrow Transplantation, Department of Pediatrics, University of Minnesota Cancer Center, Minneapolis, MN
Renata Widelak
1Division of Pediatric Blood and Marrow Transplantation, Department of Pediatrics, University of Minnesota Cancer Center, Minneapolis, MN
Angela Panoskaltsis-Mortari
Megan J. Riddle
1Division of Pediatric Blood and Marrow Transplantation, Department of Pediatrics, University of Minnesota Cancer Center, Minneapolis, MN
Jakub Tolar
1Division of Pediatric Blood and Marrow Transplantation, Department of Pediatrics, University of Minnesota Cancer Center, Minneapolis, MN
Cindy Eide
1Division of Pediatric Blood and Marrow Transplantation, Department of Pediatrics, University of Minnesota Cancer Center, Minneapolis, MN
Lily Xia
1Division of Pediatric Blood and Marrow Transplantation, Department of Pediatrics, University of Minnesota Cancer Center, Minneapolis, MN
Alec D. Witty
3Fate Therapeutics, San Diego, CA
Amit K. Mehta
3Fate Therapeutics, San Diego, CA
Matthew Denholtz
3Fate Therapeutics, San Diego, CA
Mehrdad Hefazi
4T Cell Engineering Laboratory and the Division of Hematology, Mayo Clinic, Rochester, MN
Sophia Hani
1Division of Pediatric Blood and Marrow Transplantation, Department of Pediatrics, University of Minnesota Cancer Center, Minneapolis, MN
Saad S. Kenderian
Jeffrey S. Miller
1Masonic Cancer Center, University of Minnesota, Minneapolis, MN
Jeffrey J. Molldrem
Leslie S. Kean
Dana–Farber Cancer Institute–Boston Children’s Hospital, Boston
Bahram Valamehr
1Fate therapeutics, Research and development, San Diego, United States
Bruce R. Blazar
Department of Pediatrics, Division of Blood & Marrow Transplant & Cellular Therapy, University of Minnesota