ER stress regulates myeloid-derived suppressor cell fate through TRAIL-R-mediated apoptosis.
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.
Thomas
T
Condamine
Vinit
V
Kumar
Indu R
IR
Ramachandran
Je-In
JI
Youn
Esteban
E
Celis
Niklas
N
Finnberg
Wafik S
WS
El-Deiry
Rafael
R
Winograd
Robert H
RH
Vonderheide
Nickolas R
NR
English
Stella C
SC
Knight
Hideo
H
Yagita
Judith C
JC
McCaffrey
Scott
S
Antonia
Neil
N
Hockstein
Robert
R
Witt
Gregory
G
Masters
Thomas
T
Bauer
Dmitry I
DI
Gabrilovich
D000818:Animals; D017209:Apoptosis / Q000276:immunology; D002289:Carcinoma, Non-Small-Cell Lung / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D059865:Endoplasmic Reticulum Stress; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008954:Models, Biological; D022423:Myeloid Cells / Q000276:immunology* / Q000378:metabolism* / Q000473:pathology; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand / Q000378:metabolism*
D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand