GVHD-associated, inflammasome-mediated loss of function in adoptively transferred myeloid-derived suppressor cells.
Myeloid-derived suppressor cells (MDSCs) are a naturally occurring immune regulatory population associated with inhibition of ongoing inflammatory responses. In vitro generation of MDSCs from bone marrow has been shown to enhance survival in an acute model of lethal graft-versus-host disease (GVHD). However, donor MDSC infusion only partially ameliorates GVHD lethality. In order to improve the potential therapeutic benefit and ultimately survival outcomes, we set out to investigate the fate of MDSCs after transfer in the setting of acute GVHD (aGVHD). MDSCs transferred to lethally irradiated recipients of allogeneic donor hematopoietic grafts are exposed to an intense inflammatory environment associated with aGVHD, which we now show directly undermines their suppressive capacity. Under a conditioning regimen and GVHD inflammatory settings, MDSCs rapidly lose suppressor function and their potential to inhibit GVHD lethality, which is associated with their induced conversion toward a mature inflammasome-activated state. We find even brief in vitro exposure to inflammasome-activating mediators negates the suppressive potential of cultured murine and human-derived MDSCs. Consistent with a role for the inflammasome, donor MDSCs deficient in the adaptor ASC (apoptosis-associated speck-like protein containing a CARD), which assembles inflammasome complexes, conferred improved survival of mice developing GVHD compared with wild-type donor MDSCs. These data suggest the use of MDSCs as a therapeutic approach for preventing GVHD and other systemic inflammatory conditions will be more effective when combined with approaches limiting in vivo MDSC inflammasome activation, empowering MDSCs to maintain their suppressive potential.
Department of Pediatrics, Division of Blood and Marrow Transplantation, University of Minnesota Cancer Center, Minneapolis, MN;
Brent H
BH
Koehn
Department of Hematology and Oncology, Freiburg University Medical Center, Albert-Ludwigs-University, Freiburg, Germany;
Petya
P
Apostolova
Departments of Infectious Diseases and Immunology, St. Jude Children's Research Hospital, Memphis, TN;
Jessica M
JM
Haverkamp
Blood and Marrow Transplant Program, Division of Hematology, Oncology and Transplantation, University of Minnesota Cancer Center, Minneapolis, MN;
Jeffrey S
JS
Miller
Blood and Marrow Transplant Program, Division of Hematology, Oncology and Transplantation, University of Minnesota Cancer Center, Minneapolis, MN;
Valarie
V
McCullar
Department of Pediatrics, Division of Blood and Marrow Transplantation, University of Minnesota Cancer Center, Minneapolis, MN;
Jakub
http://orcid.org/0000-0002-0957-4380
J
Tolar
Cancer Center and Department of Pediatrics, Georgia Regent's University, Augusta, GA;
David H
DH
Munn
Departments of Dermatology and Internal Medicine, School of Medicine, University of California, Davis, Sacramento, CA;
William J
WJ
Murphy
Lineberger Comprehensive Cancer Center, Inflammatory Diseases Institute, Departments of Genetics and Microbiology and Immunology, University of North Carolina, Chapel Hill, NC;
Willie June
http://orcid.org/0000-0002-6503-539X
WJ
Brickey
Lineberger Comprehensive Cancer Center, Inflammatory Diseases Institute, Departments of Genetics and Microbiology and Immunology, University of North Carolina, Chapel Hill, NC;
Jonathan S
JS
Serody
The Wistar Institute, Philadelphia, PA;
Dmitry I
http://orcid.org/0000-0001-9913-6407
DI
Gabrilovich
Dipartimento di afferenza Medicina, Verona University, Verona, Italy; and.
Vincenzo
V
Bronte
Departments of Infectious Diseases and Immunology, St. Jude Children's Research Hospital, Memphis, TN;
Peter J
http://orcid.org/0000-0001-6329-9802
PJ
Murray
Lineberger Comprehensive Cancer Center, Inflammatory Diseases Institute, Departments of Genetics and Microbiology and Immunology, University of North Carolina, Chapel Hill, NC;
Jenny P-Y
JP
Ting
Department of Hematology and Oncology, Freiburg University Medical Center, Albert-Ludwigs-University, Freiburg, Germany; Centre for Biological Signaling Studies BIOSS, Freiburg, Germany.
Robert
R
Zeiser
Department of Pediatrics, Division of Blood and Marrow Transplantation, University of Minnesota Cancer Center, Minneapolis, MN;
Bruce R
http://orcid.org/0000-0002-9608-9841
BR
Blazar
D019264:Adoptive Transfer; D000818:Animals; D001854:Bone Marrow Cells / Q000166:cytology; D018845:CD11 Antigens / Q000276:immunology; D002454:Cell Differentiation; D002478:Cells, Cultured; D006086:Graft vs Host Disease / Q000276:immunology* / Q000473:pathology / Q000628:therapy*; D006801:Humans; D058847:Inflammasomes / Q000276:immunology*; D053583:Interleukin-1beta / Q000276:immunology; D051379:Mice; D022423:Myeloid Cells / Q000166:cytology / Q000276:immunology* / Q000473:pathology / Q000637:transplantation*
D018845:CD11 Antigens; D058847:Inflammasomes; D053583:Interleukin-1beta