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
Affiliations
- Brian C. Betts
- Department of Blood and Marrow Transplantation and Cellular Immunotherapy, Tampa, FL, United States
- Brian C. Betts
- Department of Immunology, Moffitt Cancer Center, Tampa, FL, United States
- Brian C. Betts
- Division of Hematology, Oncology, and Transplantation, University of Minnesota, Minneapolis, MN, United States
- Frederick L. Locke
- Department of Blood and Marrow Transplantation and Cellular Immunotherapy, Tampa, FL, United States
- Frederick L. Locke
- Department of Immunology, Moffitt Cancer Center, Tampa, FL, United States
- Elizabeth M. Sagatys
- Department of Hematopathology and Laboratory Medicine, Moffitt Cancer Center, Tampa, FL, United States
- Joseph Pidala
- Department of Blood and Marrow Transplantation and Cellular Immunotherapy, Tampa, FL, United States
- Joseph Pidala
- Department of Immunology, Moffitt Cancer Center, Tampa, FL, United States
- Kelly Walton
- Department of Immunology, Moffitt Cancer Center, Tampa, FL, United States
- Kelly Walton
- Division of Hematology, Oncology, and Transplantation, University of Minnesota, Minneapolis, MN, United States
- Meghan Menges
- Department of Immunology, Moffitt Cancer Center, Tampa, FL, United States
- Jordan Reff
- Department of Immunology, Moffitt Cancer Center, Tampa, FL, United States
- Asim Saha
- Division of Blood and Marrow Transplantation, Department of Pediatrics, Masonic Cancer Center, University of Minnesota, Minneapolis, MN, United States
- Asim Saha
- The Center for Immunology, University of Minnesota Medical School, Minneapolis, MN, United States
- Julie Y. Djeu
- Department of Immunology, Moffitt Cancer Center, Tampa, FL, United States
- John V. Kiluk
- Comprehensive Breast Program, Moffitt Cancer Center, Tampa, FL, United States
- Marie C. Lee
- Comprehensive Breast Program, Moffitt Cancer Center, Tampa, FL, United States
- Jongphil Kim
- Department of Biostatistics and Bioinformatics, Moffitt Cancer Center, Tampa, FL, United States
- Chang Won Kang
- Department of Chemistry, University of South Florida, Tampa, FL, United States
- Chih-Hang Anthony Tang
- 0Department of Translational Tumor Immunology, The Wistar Institute, Philadelphia, PA, United States
- Jeremy Frieling
- 1Department of Tumor Biology, Moffitt Cancer Center, Tampa, FL, United States
- Conor C. Lynch
- 1Department of Tumor Biology, Moffitt Cancer Center, Tampa, FL, United States
- Alan List
- 2Department of Malignant Hematology, Moffitt Cancer Center, Tampa, FL, United States
- Paulo C. Rodriguez
- Department of Immunology, Moffitt Cancer Center, Tampa, FL, United States
- Bruce R. Blazar
- Division of Blood and Marrow Transplantation, Department of Pediatrics, Masonic Cancer Center, University of Minnesota, Minneapolis, MN, United States
- Bruce R. Blazar
- The Center for Immunology, University of Minnesota Medical School, Minneapolis, MN, United States
- Jose R. Conejo-Garcia
- Department of Immunology, Moffitt Cancer Center, Tampa, FL, United States
- Juan R. Del Valle
- Department of Chemistry, University of South Florida, Tampa, FL, United States
- Chih-Chi Andrew Hu
- 0Department of Translational Tumor Immunology, The Wistar Institute, Philadelphia, PA, United States
- Claudio Anasetti
- Department of Blood and Marrow Transplantation and Cellular Immunotherapy, Tampa, FL, United States
- Claudio Anasetti
- Department of Immunology, Moffitt Cancer Center, Tampa, FL, United States
- DOI
- https://doi.org/10.3389/fimmu.2018.02887
- Journal volume & issue
-
Vol. 9
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.
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