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

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122 Scopus citations

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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ASJC Scopus subject areas

  • Medicine(all)

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Condamine, T., Kumar, V., Ramachandran, I. R., Youn, J. I., Celis, E., Finnberg, N., El-Deiry, W. S., Winograd, R., Vonderheide, R. H., English, N. R., Knight, S. C., Yagita, H., McCaffrey, J. C., Antonia, S., Hockstein, N., Witt, R., Masters, G., Bauer, T., & 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