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.
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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 3

TRAIL-R is a potential target for MDSC removal.

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TRAIL-R is a potential target for MDSC removal. (A) IMCs and MDSCs (2 × ...
(A) IMCs and MDSCs (2 × 105 plated) were cultured in complete media overnight in the presence of different concentrations of recombinant OPG. Results represent the average number of cells recovered at the end of culture (n = 3). (B and C) Congenic CD45.1+ WT mice were lethally irradiated and reconstituted with WT or Dr5 KO BM cells. (B) 3 weeks after tumor inoculation, mice were sacrificed, and the presence of CD11b+Gr1+ MDSCs in spleen and liver was analyzed. (C) MDSCs were isolated from spleens and cultured in complete media. After 3 hours, the percentage of cleaved caspase-3+ cells was assessed by flow cytometry (results are representative of 5 experiments). (D) Number of cells recovered after overnight culture of 2 × 105 MDSCs (results of 5 different samples). (E and F) Naive CD45.1+ mice were lethally irradiated and reconstituted with a 1:1 mix of BM cells from CD45.2+ Dr5 KO and CD45.1+ WT mice (106 cells). 5 weeks after reconstitution, mice were inoculated s.c. with EL4 cells, and spleens were collected 3 weeks later. The percentage of WT (CD45.1+) and Dr5 KO (CD45.2+) cells was analyzed in spleens among different cell populations. (E) Typical example of results. (F) Cumulative results of 3 experiments. *P < 0.05; **P < 0.01.