ER stress regulates myeloid-derived suppressor cell fate through TRAIL-R-mediated apoptosis

Thomas Condamine, Vinit Kumar, Indu R. Ramachandran, Je In Youn, Esteban Celis, Niklas Finnberg, Wafik S. El-Deiry, Rafael Winograd, Robert H. Vonderheide, Nickolas R. English, Stella C. Knight, Hideo Yagita, Judith C. McCaffrey, Scott Antonia, Neil Hockstein, Robert Witt, Gregory Masters, Thomas Bauer, Dmitry I. Gabrilovich

Research output: Contribution to journalArticle

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Abstract

Myeloid-derived suppressor cells (MDSCs) dampen the immune response thorough inhibition of T cell activation and proliferation and often are expanded in pathological conditions. Here, we studied the fate of MDSCs in cancer. Unexpectedly, MDSCs had lower viability and a shorter half-life in tumor-bearing mice compared with neutrophils and monocytes. The reduction of MDSC viability was due to increased apoptosis, which was mediated by increased expression of TNF-related apoptosis-induced ligand receptors (TRAIL-Rs) in these cells. Targeting TRAIL-Rs in naive mice did not affect myeloid cell populations, but it dramatically reduced the presence of MDSCs and improved immune responses in tumor-bearing mice. Treatment of myeloid cells with proinflammatory cytokines did not affect TRAIL-R expression; however, induction of ER stress in myeloid cells recapitulated changes in TRAIL-R expression observed in tumor-bearing hosts. The ER stress response was detected in MDSCs isolated from cancer patients and tumor-bearing mice, but not in control neutrophils or monocytes, and blockade of ER stress abrogated tumor-associated changes in TRAIL-Rs. Together, these data indicate that MDSC pathophysiology is linked to ER stress, which shortens the lifespan of these cells in the periphery and promotes expansion in BM. Furthermore, TRAIL-Rs can be considered as potential targets for selectively inhibiting MDSCs.

Original languageEnglish (US)
Pages (from-to)2626-2639
Number of pages14
JournalJournal of Clinical Investigation
Volume124
Issue number6
DOIs
StatePublished - Jun 2 2014

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Apoptosis
Myeloid Cells
Neoplasms
Ligands
Monocytes
Neutrophils
Myeloid-Derived Suppressor Cells
Half-Life
Cell Survival
Cell Proliferation
Cytokines
T-Lymphocytes
Population

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Condamine, T., Kumar, V., Ramachandran, I. R., Youn, J. I., Celis, E., Finnberg, N., ... Gabrilovich, D. I. (2014). ER stress regulates myeloid-derived suppressor cell fate through TRAIL-R-mediated apoptosis. Journal of Clinical Investigation, 124(6), 2626-2639. https://doi.org/10.1172/JCI74056

ER stress regulates myeloid-derived suppressor cell fate through TRAIL-R-mediated apoptosis. / Condamine, Thomas; Kumar, Vinit; Ramachandran, Indu R.; Youn, Je In; Celis, Esteban; Finnberg, Niklas; El-Deiry, Wafik S.; Winograd, Rafael; Vonderheide, Robert H.; English, Nickolas R.; Knight, Stella C.; Yagita, Hideo; McCaffrey, Judith C.; Antonia, Scott; Hockstein, Neil; Witt, Robert; Masters, Gregory; Bauer, Thomas; Gabrilovich, Dmitry I.

In: Journal of Clinical Investigation, Vol. 124, No. 6, 02.06.2014, p. 2626-2639.

Research output: Contribution to journalArticle

Condamine, T, Kumar, V, Ramachandran, IR, Youn, JI, Celis, E, Finnberg, N, El-Deiry, WS, Winograd, R, Vonderheide, RH, English, NR, Knight, SC, Yagita, H, McCaffrey, JC, Antonia, S, Hockstein, N, Witt, R, Masters, G, Bauer, T & Gabrilovich, DI 2014, 'ER stress regulates myeloid-derived suppressor cell fate through TRAIL-R-mediated apoptosis', Journal of Clinical Investigation, vol. 124, no. 6, pp. 2626-2639. https://doi.org/10.1172/JCI74056
Condamine, Thomas ; Kumar, Vinit ; Ramachandran, Indu R. ; Youn, Je In ; Celis, Esteban ; Finnberg, Niklas ; El-Deiry, Wafik S. ; Winograd, Rafael ; Vonderheide, Robert H. ; English, Nickolas R. ; Knight, Stella C. ; Yagita, Hideo ; McCaffrey, Judith C. ; Antonia, Scott ; Hockstein, Neil ; Witt, Robert ; Masters, Gregory ; Bauer, Thomas ; Gabrilovich, Dmitry I. / ER stress regulates myeloid-derived suppressor cell fate through TRAIL-R-mediated apoptosis. In: Journal of Clinical Investigation. 2014 ; Vol. 124, No. 6. pp. 2626-2639.
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