Frontiers in Immunology (Dec 2018)

Inhibition of Human Dendritic Cell ER Stress Response Reduces T Cell Alloreactivity Yet Spares Donor Anti-tumor Immunity

  • Brian C. Betts,
  • Brian C. Betts,
  • Brian C. Betts,
  • Frederick L. Locke,
  • Frederick L. Locke,
  • Elizabeth M. Sagatys,
  • Joseph Pidala,
  • Joseph Pidala,
  • Kelly Walton,
  • Kelly Walton,
  • Meghan Menges,
  • Jordan Reff,
  • Asim Saha,
  • Asim Saha,
  • Julie Y. Djeu,
  • John V. Kiluk,
  • Marie C. Lee,
  • Jongphil Kim,
  • Chang Won Kang,
  • Chih-Hang Anthony Tang,
  • Jeremy Frieling,
  • Conor C. Lynch,
  • Alan List,
  • Paulo C. Rodriguez,
  • Bruce R. Blazar,
  • Bruce R. Blazar,
  • Jose R. Conejo-Garcia,
  • Juan R. Del Valle,
  • Chih-Chi Andrew Hu,
  • Claudio Anasetti,
  • Claudio Anasetti

DOI
https://doi.org/10.3389/fimmu.2018.02887
Journal volume & issue
Vol. 9

Abstract

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Acute graft- vs. -host disease (GVHD) is an important cause of morbidity and death after allogeneic hematopoietic cell transplantation (HCT). We identify a new approach to prevent GVHD that impairs monocyte-derived dendritic cell (moDC) alloactivation of T cells, yet preserves graft- vs.-leukemia (GVL). Exceeding endoplasmic reticulum (ER) capacity results in a spliced form of X-box binding protein-1 (XBP-1s). XBP-1s mediates ER stress and inflammatory responses. We demonstrate that siRNA targeting XBP-1 in moDCs abrogates their stimulation of allogeneic T cells. B-I09, an inositol-requiring enzyme-1α (IRE1α) inhibitor that prevents XBP-1 splicing, reduces human moDC migration, allo-stimulatory potency, and curtails moDC IL-1β, TGFβ, and p40 cytokines, suppressing Th1 and Th17 cell priming. B-I09-treated moDCs reduce responder T cell activation via calcium flux without interfering with regulatory T cell (Treg) function or GVL effects by cytotoxic T lymphocytes (CTL) and NK cells. In a human T cell mediated xenogeneic GVHD model, B-I09 inhibition of XBP-1s reduced target-organ damage and pathogenic Th1 and Th17 cells without impacting donor Tregs or anti-tumor CTL. DC XBP-1s inhibition provides an innovative strategy to prevent GVHD and retain GVL.

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