Cdk5 disruption attenuates tumor PD-L1 expression and promotes antitumor immunity

作者：Rodney Dixon Dorand, Joseph M. Nthale, Jay Myers, Deborah Sim Barkauskas, Stefanie Avril, Steven M. Chirieleison, Tej Kumar Pareek, Derek W. Abbott, Duncan S. Stearns, John J. Letterio, Alex Yee-Chen Huang, Agnė Petrošiūtė · 发表于：Science · 年份：2016 · DOI：10.1126/science.aae0477 · 被引用次数：320 · 研究领域：Cancer Immunotherapy and Biomarkers、Cancer Mechanisms and Therapy、Immune cells in cancer

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-γ (IFN-γ)-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.