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

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

Author information

1
Department of Blood and Marrow Transplantation and Cellular Immunotherapy, Tampa, FL, United States.
2
Department of Immunology, Moffitt Cancer Center, Tampa, FL, United States.
3
Division of Hematology, Oncology, and Transplantation, University of Minnesota, Minneapolis, MN, United States.
4
Department of Hematopathology and Laboratory Medicine, Moffitt Cancer Center, Tampa, FL, United States.
5
Division of Blood and Marrow Transplantation, Department of Pediatrics, Masonic Cancer Center, University of Minnesota, Minneapolis, MN, United States.
6
The Center for Immunology, University of Minnesota Medical School, Minneapolis, MN, United States.
7
Comprehensive Breast Program, Moffitt Cancer Center, Tampa, FL, United States.
8
Department of Biostatistics and Bioinformatics, Moffitt Cancer Center, Tampa, FL, United States.
9
Department of Chemistry, University of South Florida, Tampa, FL, United States.
10
Department of Translational Tumor Immunology, The Wistar Institute, Philadelphia, PA, United States.
11
Department of Tumor Biology, Moffitt Cancer Center, Tampa, FL, United States.
12
Department of Malignant Hematology, Moffitt Cancer Center, Tampa, FL, United States.

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

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