Myeloid-derived suppressor cells (MDSCs) can subdue inflammation. In mice with acute graft-versus-host disease (GVHD), donor MDSC infusion enhances survival that is only partial and transient because of MDSC inflammasome activation early posttransfer, resulting in differentiation and loss of suppressor function. Here we demonstrate that conditioning regimen-induced adenosine triphosphate (ATP) release is a primary driver of MDSC dysfunction through ATP receptor (P2x7R) engagement and NLR pyrin family domain 3 (NLRP3) inflammasome activation. P2x7R or NLRP3 knockout (KO) donor MDSCs provided significantly higher survival than wild-type (WT) MDSCs. Although in vivo pharmacologic targeting of NLRP3 or P2x7R promoted recipient survival, indicating in vivo biologic effects, no synergistic survival advantage was seen when combined with MDSCs. Because activated inflammasomes release mature interleukin-1β (IL-1β), we expected that IL-1β KO donor MDSCs would be superior in subverting GVHD, but such MDSCs proved inferior relative to WT. IL-1β release and IL-1 receptor expression was required for optimal MDSC function, and exogenous IL-1β added to suppression assays that included MDSCs increased suppressor potency. These data indicate that prolonged systemic NLRP3 inflammasome inhibition and decreased IL-1β could diminish survival in GVHD. However, loss of inflammasome activation and IL-1β release restricted to MDSCs rather than systemic inhibition allowed non-MDSC IL-1β signaling, improving survival. Extracellular ATP catalysis with peritransplant apyrase administered into the peritoneum, the ATP release site, synergized with WT MDSCs, as did regulatory T-cell infusion, which we showed reduced but did not eliminate MDSC inflammasome activation, as assessed with a novel inflammasome reporter strain. These findings will inform future clinical using MDSCs to decrease alloresponses in inflammatory environments.
Bibliographical noteFunding Information:
This study was supported by National Institutes of Health Research Program Grants from the National Heart, Lung, and Blood Institue (R01 HL56067), National Institue of Allergy and Infectious Diseases (R37 AI34495), and National Heart, Lung, and Blood Institue (R01 HL11879).
Conflict-of-interest disclosure: B.R.B. receives remuneration as an advisor to Kadmon Pharmaceuticals, Inc., Five Prime Therapeutics, Inc., Regeneron Pharmaceuticals, Magenta Therapeutics, and BlueRock Therapeutics and research support from Fate Therapeutics, RXi Pharmaceuticals, Alpine Immune Sciences, Inc., AbbVie, Inc., the Leukemia and Lymphoma Society, the Children’s Cancer Research Fund, and the KidsFirst Fund and is a cofounder of Tmunity Therapuetics, Inc.; C.J.F. is an employee of Novartis Pharma AG; J.S.M. receives remuneration as a consultant to and receives research funds from Fate Therapeutics and GT Biopharma and serves on the scientific advisory boards of OnkImmune, Dr Reddy’s Laboratories, Moderna, Nektar, and CytoSen; and B.H.K., R.Z., P.J.M., V.B., and B.R.B. disclose patent licensing to Fate Therapeutics, Inc. The remaining authors declare no competing financial interests.