期刊
SCIENCE
卷 353, 期 6297, 页码 399-403出版社
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/science.aae0477
关键词
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资金
- NIH [F31CA196265, T32GM007250, T32AI089474, R01GM086550, R01CA154656, R21CA181875, R01HL111682, P30CA043703]
- Wolstein Research Scholarship
- St. Baldrick's Foundation
- Hyundai Hope-on-Wheels Program
- Marc Joseph Fund
- Alex's Lemonade Stand Foundation
- Angie Fowler Adolescent and Young Adult Cancer Research Initiative at the Case Comprehensive Cancer Center
- Theresia G. and Stuart F. Kline Family Foundation in Pediatric Oncology
- Clinical and Translational Science Collaborative of Cleveland from the National Center for Advancing Translational Sciences (NCATS) component of the NIH [UL1TR000439, KL2TR000440]
Cancers often evade immune surveillance by adopting peripheral tissue-tolerance mechanisms, such as the expression of programmed cell death ligand 1 (PD-L1), the inhibition of which results in potent antitumor immunity. Here, we show that cyclin-dependent kinase 5 (Cdk5), a serine-threonine kinase that is highly active in postmitotic neurons and in many cancers, allows medulloblastoma (MB) to evade immune elimination. Interferon-gamma (IFN-gamma)-induced PD-L1 up-regulation on MB requires Cdk5, and disruption of Cdk5 expression in a mouse model of MB results in potent CD4(+) T cell-mediated tumor rejection. Loss of Cdk5 results in persistent expression of the PD-L1 transcriptional repressors, the interferon regulatory factors IRF2 and IRF2BP2, which likely leads to reduced PD-L1 expression on tumors. Our finding highlights a central role for Cdk5 in immune checkpoint regulation by tumor cells.
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