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

Front Immunol. 2018 Dec 6;9:2887. doi: 10.3389/fimmu.2018.02887. eCollection 2018.

Abstract

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.

Keywords: GvHD; GvL; XBP-1S; dendritic cell (DC); er stress.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Line, Tumor
  • Dendritic Cells / drug effects
  • Dendritic Cells / immunology*
  • Dendritic Cells / metabolism
  • Endoplasmic Reticulum Stress / drug effects
  • Endoplasmic Reticulum Stress / immunology
  • Endoribonucleases / antagonists & inhibitors
  • Endoribonucleases / metabolism
  • Enzyme Inhibitors / pharmacology
  • Female
  • Gene Knockdown Techniques
  • Graft vs Host Disease / immunology
  • Graft vs Host Disease / prevention & control*
  • Graft vs Leukemia Effect / immunology
  • Hematopoietic Stem Cell Transplantation / adverse effects*
  • Humans
  • Immunosuppression / methods*
  • Inflammasomes / drug effects
  • Inflammasomes / immunology
  • Inflammasomes / metabolism
  • Isoantibodies / immunology
  • Isoantibodies / metabolism
  • Isoantigens / immunology
  • Leukemia / immunology
  • Leukemia / therapy*
  • Lymphocyte Activation / drug effects
  • Male
  • Mice
  • Protein-Serine-Threonine Kinases / antagonists & inhibitors
  • Protein-Serine-Threonine Kinases / metabolism
  • RNA, Small Interfering / metabolism
  • Skin Transplantation
  • T-Lymphocyte Subsets / immunology
  • T-Lymphocyte Subsets / metabolism
  • Transplantation Chimera
  • Transplantation, Homologous / adverse effects
  • X-Box Binding Protein 1 / antagonists & inhibitors*
  • X-Box Binding Protein 1 / genetics
  • X-Box Binding Protein 1 / immunology
  • X-Box Binding Protein 1 / metabolism
  • Xenograft Model Antitumor Assays

Substances

  • Enzyme Inhibitors
  • Inflammasomes
  • Isoantibodies
  • Isoantigens
  • RNA, Small Interfering
  • X-Box Binding Protein 1
  • XBP1 protein, human
  • ERN1 protein, human
  • Protein-Serine-Threonine Kinases
  • Endoribonucleases