Danger-associated extracellular ATP counters MDSC therapeutic efficacy in acute GVHD

Brent H. Koehn, Asim Saha, Cameron McDonald-Hyman, Michael Loschi, Govindarajan Thangavelu, Lie Ma, Michael Zaiken, Josh Dysthe, Walker Krepps, Jamie Panthera, Keli Hippen, Stephen C. Jameson, Jeffrey S. Miller, Matthew A. Cooper, Christopher J. Farady, Takao Iwawaki, Jenny P.Y. Ting, Jonathan S. Serody, William J. Murphy, Geoffrey R. HillPeter J. Murray, Vincenzo Bronte, David H. Munn, Robert Zeiser, Bruce R. Blazar

Research output: Contribution to journalArticle

6 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)1670-1682
Number of pages13
JournalBlood
Volume134
Issue number19
DOIs
StatePublished - Nov 7 2019

ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

Fingerprint Dive into the research topics of 'Danger-associated extracellular ATP counters MDSC therapeutic efficacy in acute GVHD'. Together they form a unique fingerprint.

  • Cite this

    Koehn, B. H., Saha, A., McDonald-Hyman, C., Loschi, M., Thangavelu, G., Ma, L., Zaiken, M., Dysthe, J., Krepps, W., Panthera, J., Hippen, K., Jameson, S. C., Miller, J. S., Cooper, M. A., Farady, C. J., Iwawaki, T., Ting, J. P. Y., Serody, J. S., Murphy, W. J., ... Blazar, B. R. (2019). Danger-associated extracellular ATP counters MDSC therapeutic efficacy in acute GVHD. Blood, 134(19), 1670-1682. https://doi.org/10.1182/blood.2019001950