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

Brian Betts, Frederick L. Locke, Elizabeth M. Sagatys, Joseph Pidala, Kelly Walton, Meghan Menges, Jordan Reff, 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, Jose R. Conejo-Garcia & 3 others Juan R. Del Valle, Chih Chi Andrew Hu, Claudio Anasetti

Research output: Contribution to journalArticle

3 Citations (Scopus)

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.

Original languageEnglish (US)
Number of pages1
JournalFrontiers in immunology
Volume9
DOIs
StatePublished - Jan 1 2018

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Endoplasmic Reticulum Stress
Dendritic Cells
Immunity
T-Lymphocytes
Th17 Cells
Monocytes
Th1 Cells
Cytotoxic T-Lymphocytes
Neoplasms
Transplants
Cell Transplantation
Enzyme Inhibitors
Inositol
Regulatory T-Lymphocytes
Interleukin-1
Natural Killer Cells
Endoplasmic Reticulum
Small Interfering RNA
Cell Movement
Cause of Death

Keywords

  • GvHD
  • GvL
  • XBP-1S
  • dendritic cell (DC)
  • er stress

PubMed: MeSH publication types

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

Cite this

Inhibition of Human Dendritic Cell ER Stress Response Reduces T Cell Alloreactivity Yet Spares Donor Anti-tumor Immunity. / Betts, Brian; Locke, Frederick L.; Sagatys, Elizabeth M.; Pidala, Joseph; Walton, Kelly; Menges, Meghan; Reff, Jordan; Saha, Asim; Djeu, Julie Y.; Kiluk, John V.; Lee, Marie C.; Kim, Jongphil; Kang, Chang Won; Tang, Chih Hang Anthony; Frieling, Jeremy; Lynch, Conor C.; List, Alan; Rodriguez, Paulo C.; Blazar, Bruce R; Conejo-Garcia, Jose R.; Del Valle, Juan R.; Hu, Chih Chi Andrew; Anasetti, Claudio.

In: Frontiers in immunology, Vol. 9, 01.01.2018.

Research output: Contribution to journalArticle

Betts, B, Locke, FL, Sagatys, EM, Pidala, J, Walton, K, Menges, M, Reff, J, Saha, A, Djeu, JY, Kiluk, JV, Lee, MC, Kim, J, Kang, CW, Tang, CHA, Frieling, J, Lynch, CC, List, A, Rodriguez, PC, Blazar, BR, Conejo-Garcia, JR, Del Valle, JR, Hu, CCA & Anasetti, C 2018, 'Inhibition of Human Dendritic Cell ER Stress Response Reduces T Cell Alloreactivity Yet Spares Donor Anti-tumor Immunity', Frontiers in immunology, vol. 9. https://doi.org/10.3389/fimmu.2018.02887
Betts, Brian ; Locke, Frederick L. ; Sagatys, Elizabeth M. ; Pidala, Joseph ; Walton, Kelly ; Menges, Meghan ; Reff, Jordan ; Saha, Asim ; Djeu, Julie Y. ; Kiluk, John V. ; Lee, Marie C. ; Kim, Jongphil ; Kang, Chang Won ; Tang, Chih Hang Anthony ; Frieling, Jeremy ; Lynch, Conor C. ; List, Alan ; Rodriguez, Paulo C. ; Blazar, Bruce R ; Conejo-Garcia, Jose R. ; Del Valle, Juan R. ; Hu, Chih Chi Andrew ; Anasetti, Claudio. / Inhibition of Human Dendritic Cell ER Stress Response Reduces T Cell Alloreactivity Yet Spares Donor Anti-tumor Immunity. In: Frontiers in immunology. 2018 ; Vol. 9.
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AU - Pidala, Joseph

AU - Walton, Kelly

AU - Menges, Meghan

AU - Reff, Jordan

AU - Saha, Asim

AU - Djeu, Julie Y.

AU - Kiluk, John V.

AU - Lee, Marie C.

AU - Kim, Jongphil

AU - Kang, Chang Won

AU - Tang, Chih Hang Anthony

AU - Frieling, Jeremy

AU - Lynch, Conor C.

AU - List, Alan

AU - Rodriguez, Paulo C.

AU - Blazar, Bruce R

AU - Conejo-Garcia, Jose R.

AU - Del Valle, Juan R.

AU - Hu, Chih Chi Andrew

AU - Anasetti, Claudio

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N2 - 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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