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

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 2

MDSCs undergo rapid apoptosis mediated by upregulation of DR5 expression.

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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.