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.
View: Text | PDF
Research Article Immunology Article has an altmetric score of 24

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

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

×

Figure 6

ER stress response drives TRAIL-R upregulation in MDSCs.

Options: View larger image (or click on image) Download as PowerPoint
ER stress response drives TRAIL-R upregulation in MDSCs. (A and B) Hemat...
(A and B) Hematopoietic progenitor cells were cultured for 5 days in the presence of 20 ng/ml GM-CSF. (A) DR5 expression on the surface of PMNs stimulated for 24 hours in the presence of IL-1β, TNF-α, IL-6, IFN-γ, or tunicamycin (TUN) or left unstimulated (NS). Results of 3 experiments are shown. (B) DR5 expression on the surface of PMNs and monocytes stimulated with tunicamycin (dotted line) or left unstimulated (solid line) for 24 hours. Gray filled histogram, isotype control. Shown is 1 representative experiment of 4. (C and D) Purified PMNs from BM were treated overnight with thapsigargin (THG) or left untreated. DR5 expression (C) and cell viability (D) were assessed by flow cytometry (n = 3). (E and F) Electron microscopy analysis of cell morphology. PMNs and PMN-MDSCs (E) and monocytes and M-MDSCs (F) were isolated from spleen of control and EL4 TB mice. Shown are representative microphotographs (arrows denote ER dilation) and the proportion of cells with each ER dilation score (see Methods). Scale bars: 1 μm. (G) Chop, Xbp1, Atf4, and Bip expression in splenic PMNs and PMN-MDSCs, determined using quantitative RT-PCR. Results are from 3 different samples. (H and I) Spliced XBP1 and CHOP in PMNs and PMN-MDSCs from EL4 TB mice (H) or KPC TB mice (spleen cells only; I), determined by Western blot. Results are representative of 4 different samples. *P < 0.05; **P < 0.01.