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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 7

Human MDSC survival and TRAIL-R expression.

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Human MDSC survival and TRAIL-R expression.
(A) Human PMN-MDSCs and PMNs...
(A) Human PMN-MDSCs and PMNs were isolated from blood of NSCLC patients and cultured overnight in complete media. The percentage of cells was determined by flow cytometry at the beginning and end of culture, and the total number of surviving PMN-MDSCs and PMNs was calculated (n = 3). (B and C) Human PMN-MDSCs and PMNs were cultured in complete media supplemented with 10 ng/ml GM-CSF, in the presence of agonistic anti-DR5 mAb (200 ng/ml) (B) or recombinant TRAIL (100 ng/ml) (C), and the percentage of surviving cells was determined (n = 3). (D) DR4, DR5, DCR1, and DCR2 expression on the surface of PMN-MDSCs and PMNs from the blood of healthy donors (HD) or NSCLC patients. (E) DCR1 and DCR2 expression in PMNs (solid line) and PMN-MDSCs (dotted line). Gray filled histogram, isotype control. Results show a typical example of 6 different patient samples. (F) DR5, DCR1, and DCR2 expression on the surface of blood or tumor PMN-MDSCs from 5 HNC patients and PMNs from healthy donors. *P < 0.05; **P < 0.01.

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

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