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

• Published in: Science (American Association for the Advancement of Science) Vol. 353; no. 6297; pp. 399 - 403
• Main Authors: Dorand, R. Dixon, Nthale, Joseph, Myers, Jay T., Barkauskas, Deborah S., Avril, Stefanie, Chirieleison, Steven M., Pareek, Tej K., Abbott, Derek W., Stearns, Duncan S., Letterio, John J., Huang, Alex Y., Petrosiute, Agne
• Format: Journal Article
• Language: English
• Published: United States American Association for the Advancement of Science 22-07-2016; The American Association for the Advancement of Science
• Subjects: Animals; B7-H1 Antigen - genetics; Brain cancer; Cancer; CD4-Positive T-Lymphocytes - immunology; Cell death; Cell Line, Tumor; Cerebellar Neoplasms - genetics; Cerebellar Neoplasms - immunology; Cyclin-Dependent Kinase 5 - genetics; Cyclin-Dependent Kinase 5 - physiology; Cyclin-dependent kinases; Disruption; Gene Expression Regulation, Neoplastic; Humans; Immunity; Immunologic Surveillance; Immunotherapy; Interferon Regulatory Factor-2 - genetics; Interferon Regulatory Factor-2 - metabolism; Kinases; Male; Medulloblastoma - immunology; Mice; Mice, Inbred C57BL; Mice, Nude; Neoplasms, Experimental - genetics; Neoplasms, Experimental - immunology; Neurons; Palladium; T cell receptors; Transcription Factors - genetics; Transcription Factors - metabolism; Tumor Escape - genetics; Tumors
• ISSN: 0036-8075; 1095-9203
• DOI: 10.1126/science.aae0477

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 cyclindependent 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.