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 1

MDSCs have shorter survival than their naive counterparts.

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MDSCs have shorter survival than their naive counterparts. (A–C) BrdU pu...
(A–C) BrdU pulse-chase analysis of MDSC turnover (n = 3 mice per time point). (A and B) BrdU+ cells in PB monocytes and M-MDSCs (A) and in PB PMNs and PMN-MDSCs (B) during pulse. (C) BrdU+ cells in PMNs and PMN-MDSCs in blood and spleen during chase. (D–F) MDSC/IMC ratio in different organs 6 (D) or 20 (E and F) hours after i.v. injection of MDSC/IMC mix (1:1 ratio) into TB recipients. (D and E) 1 representative experiment. Cell count and percentages of boxed regions are indicated. (F) Combined results; each symbol represents 1 mouse (n = 4). (G) Recovery of myeloid cells isolated from BM or spleen of control or EL4 TB mice, after 20 hours of culture in complete media without cytokines (n = 3). 2 × 105 purified cells were plated at the beginning of culture. (H) Naive and EL4 TB mice were injected i.p. with 12% casein 20 and 4 hours prior to harvesting of peritoneal fluid. Ly6G+ cells were purified using magnetic beads and cultured overnight in complete media without cytokines. Shown is the proportion of surviving cells (relative to input) in 3 samples per group. (I) Purified IMCs and MDSCs were labeled with 2 different cell trackers (1:1 CMFDA/DDAO). Labeled cells were cultured alone in medium or mixed at a 1:5 ratio with freshly isolated splenocytes or with tumor, lung, or liver cells, then cultured overnight in complete media. The MDSC/IMC ratio was then calculated (n = 3). P values are compared with medium alone. *P < 0.05; **P < 0.01; ***P < 0.001.