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 June 2, 2014; First 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

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 2

MDSCs undergo rapid apoptosis mediated by upregulation of DR5 expression.

Options: View larger image (or click on image) Download as PowerPoint
MDSCs undergo rapid apoptosis mediated by upregulation of DR5 expression...
(A and B) Apoptosis was analyzed based on percentages of cleaved caspase-3+ cells after 3 hours in culture (A) and of annexin V+ cells after 6 hours (B). Results represent the average of 4 different experiments. (C) Amount of BCL-2, BCL-XL, cleaved caspase-8, cleaved caspase-9, and cleaved caspase-3 was determined after a 3-hour culture of cells by Western blot. 3 experiments were performed with the same results. (D) Cells were cultured in the presence of the caspase-8 inhibitor Z-IETD-FMK (100 μM) or DMSO (control), and the percentage of apoptotic cells (cleaved caspase-3+) was determined after 3 hours. Representative results of 3 different experiments are shown. (E) Receptor expression in BM IMCs or MDSCs, determined using quantitative RT-PCR. Results represent the average of 3 different samples. (F and G) DR5 expression on the surface of PMN-MDSCs (F) or M-MDSCs (G) in spleens of different TB mice or from control PMNs (F) or monocytes (G) isolated from corresponding C57BL/6 or Balb/c mice (3–5 different samples). (H) DR5 expression on the surface of PMN-MDSCs and M-MDSCs from spleen (solid line) or tumor site (dotted line) from EL4 TB mice. Gray filled histogram, isotype control. Results are representative of 4 different experiments. *P < 0.05.