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ER stress regulates myeloid-derived suppressor cell fate through TRAIL-R–mediated apoptosis
Thomas Condamine, … , Thomas Bauer, Dmitry I. Gabrilovich
Thomas Condamine, … , Thomas Bauer, Dmitry I. Gabrilovich
Published May 1, 2014
Citation Information: J Clin Invest. 2014;124(6):2626-2639. https://doi.org/10.1172/JCI74056.
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Research Article Immunology

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

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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.

Authors

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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Figure 8

ER stress response modulates TRAIL-R expression in human MDSCs.

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ER stress response modulates TRAIL-R expression in human MDSCs.
(A) Amou...
(A) Amounts of spliced XBP1 and CHOP in PMNs and PMN-MDSCs purified from healthy donor or NSCLC patient blood, determined by Western blot. Results are representative of 5 different samples. (B) Human PMNs from healthy donors were cultured in complete media supplemented with 10 ng/ml GM-CSF for 24 hours in the presence of 1 μM thapsigargin. DCR1 and DCR2 expression was assessed by flow cytometry. Shown are representative flow histograms and percentage of MFI decrease (n = 3). (C and D) Healthy donor PMNs were cultured with GM-CSF for 48 hours in the presence of 20% TCM (PCI30 cells). (C) Chop, Xbp1, Atf4, and Bip expression, determined by quantitative RT-PCR. Results represent the average of 4 different samples (D) PMNs were preincubated with 500 μg/ml TUDCA (Calbiochem) for 3 hours prior to the addition of TCM. After culture, cells were harvested, and DCR1 and DCR2 expression was analyzed. Data are mean ± SD of 4 different samples. *P < 0.05.

Copyright © 2022 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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