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 4

DR5 targeting results in selective MDSC elimination.

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DR5 targeting results in selective MDSC elimination. (A and B) Splenic P...
(A and B) Splenic PMNs and PMN-MDSCs were cultured overnight in complete media supplemented with 10 ng/ml GM-CSF, in a plate coated with MD5-1 mAb or control IgG (10 μg/ml). After 20 hours, percentages of annexin V+ cells (A) and survival (B) were determined. Results are representative of 3 different experiments. (C) Total MDSCs, PMN-MDSCs, and M-MDSCs in EL4 TB spleens, measured by flow cytometry. Treatment with control IgG and MD5-1 mAb (100 μg) was initiated on day 17 after tumor inoculation, when tumor diameter reached 1.5 cm, and repeated on days 20 and 23; mice were sacrificed on day 24. (n = 4). (D) EG7 TB mice were treated with MD5-1 mAb (100 μg) and/or anti-CD8 mAb (200 μg) or left untreated, and tumor growth was determined (n = 4 per group). (E) On day 28 after tumor inoculation, mice were sacrificed; splenic T cells were enriched and stimulated in the presence of control DCs, loaded with OVA or irrelevant protein. IFN-γ secretion was assessed by Elispot after 48 hours of restimulation (n = 3). (F) Naive (freshly isolated) or activated (3 days culture with 100 ng/ml SIINFEKL) OT-I splenocytes were stimulated with control or specific peptide (100 ng/ml SIINFEKL) in the presence of control IgG or MD5-1 mAb (10 μg/ml). IFN-γ secretion was assessed by Elispot after 48 hours of restimulation (n = 3). (G) EL4 TB mice were treated with anti-CTLA4 and/or anti–MD5-1 mAb (100 μg each) or left untreated, and tumor growth was determined (n = 4 per group). *P < 0.05; **P < 0.01.