ER stress regulates myeloid-derived suppressor cell fate through TRAIL-R–mediated apoptosis
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
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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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.