髓源性抑制细胞
促炎细胞因子
髓样
免疫系统
细胞凋亡
癌症研究
未折叠蛋白反应
生物
免疫学
肿瘤坏死因子α
细胞生物学
炎症
癌症
抑制器
遗传学
生物化学
作者
Thomas Condamine,Vinit Kumar,Indu 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 L. Witt,Gregory A. Masters,Thomas Bauer,Dmitry I. Gabrilovich
摘要
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.
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