title: Cdk5 disruption attenuates tumor PD-L1 expression and promotes antitumor immunity.
abstract: 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.
authors.affiliation: Department of Pathology, Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA. Division of Pediatric Hematology-Oncology, Department of Pediatrics, Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA.
authors.forename: R Dixon
authors.initials: RD
authors.lastname: Dorand
authors.affiliation: Division of Pediatric Hematology-Oncology, Department of Pediatrics, Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA. Angie Fowler Adolescent and Young Adult Cancer Institute and University Hospitals Rainbow Babies and Children's Hospital, Cleveland, OH 44106, USA.
authors.forename: Joseph
authors.initials: J
authors.lastname: Nthale
authors.affiliation: Division of Pediatric Hematology-Oncology, Department of Pediatrics, Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA. Angie Fowler Adolescent and Young Adult Cancer Institute and University Hospitals Rainbow Babies and Children's Hospital, Cleveland, OH 44106, USA.
authors.forename: Jay T
authors.initials: JT
authors.lastname: Myers
authors.affiliation: Division of Pediatric Hematology-Oncology, Department of Pediatrics, Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA. Angie Fowler Adolescent and Young Adult Cancer Institute and University Hospitals Rainbow Babies and Children's Hospital, Cleveland, OH 44106, USA.
authors.forename: Deborah S
authors.initials: DS
authors.lastname: Barkauskas
authors.affiliation: Department of Pathology, Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA. Case Comprehensive Cancer Center, Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA.
authors.forename: Stefanie
authors.initials: S
authors.lastname: Avril
authors.affiliation: Department of Pathology, Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA.
authors.forename: Steven M
authors.initials: SM
authors.lastname: Chirieleison
authors.affiliation: Division of Pediatric Hematology-Oncology, Department of Pediatrics, Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA. Angie Fowler Adolescent and Young Adult Cancer Institute and University Hospitals Rainbow Babies and Children's Hospital, Cleveland, OH 44106, USA.
authors.forename: Tej K
authors.initials: TK
authors.lastname: Pareek
authors.affiliation: Department of Pathology, Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA. Case Comprehensive Cancer Center, Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA.
authors.forename: Derek W
authors.initials: DW
authors.lastname: Abbott
authors.affiliation: Division of Pediatric Hematology-Oncology, Department of Pediatrics, Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA. Angie Fowler Adolescent and Young Adult Cancer Institute and University Hospitals Rainbow Babies and Children's Hospital, Cleveland, OH 44106, USA. Case Comprehensive Cancer Center, Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA.
authors.forename: Duncan S
authors.initials: DS
authors.lastname: Stearns
authors.affiliation: Division of Pediatric Hematology-Oncology, Department of Pediatrics, Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA. Angie Fowler Adolescent and Young Adult Cancer Institute and University Hospitals Rainbow Babies and Children's Hospital, Cleveland, OH 44106, USA. Case Comprehensive Cancer Center, Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA.
authors.forename: John J
authors.initials: JJ
authors.lastname: Letterio
authors.affiliation: Department of Pathology, Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA. Division of Pediatric Hematology-Oncology, Department of Pediatrics, Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA. Angie Fowler Adolescent and Young Adult Cancer Institute and University Hospitals Rainbow Babies and Children's Hospital, Cleveland, OH 44106, USA. Case Comprehensive Cancer Center, Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA. ayh3@case.edu axp125@case.edu.
authors.forename: Alex Y
authors.initials: AY
authors.lastname: Huang
authors.affiliation: Division of Pediatric Hematology-Oncology, Department of Pediatrics, Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA. Angie Fowler Adolescent and Young Adult Cancer Institute and University Hospitals Rainbow Babies and Children's Hospital, Cleveland, OH 44106, USA. Case Comprehensive Cancer Center, Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA. ayh3@case.edu axp125@case.edu.
authors.forename: Agne
authors.initials: A
authors.lastname: Petrosiute
mesh_terms: D000818:Animals; D060890:B7-H1 Antigen / Q000235:genetics*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D045744:Cell Line, Tumor; D002528:Cerebellar Neoplasms / Q000235:genetics / Q000276:immunology*; D051360:Cyclin-Dependent Kinase 5 / Q000235:genetics / Q000502:physiology*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007157:Immunologic Surveillance; D050836:Interferon Regulatory Factor-2 / Q000235:genetics / Q000378:metabolism; D008297:Male; D008527:Medulloblastoma / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008819:Mice, Nude; D009374:Neoplasms, Experimental / Q000235:genetics / Q000276:immunology*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D019139:Tumor Escape / Q000235:genetics*
chemical_list: D060890:B7-H1 Antigen; C498919:Cd274 protein, mouse; C000603862:IRF2BP2 protein, mouse; D050836:Interferon Regulatory Factor-2; C494230:Irf2 protein, mouse; D014157:Transcription Factors; D051360:Cyclin-Dependent Kinase 5; C495906:Cdk5 protein, mouse