CDK5 suppression promotes CD4+ T cell–mediated antitumor immunity in medulloblastoma.
Major finding: CDK5 suppression promotes CD4+ T cell–mediated antitumor immunity in medulloblastoma.
Mechanism: Loss of CDK5 enhances expression of IRF2 and IRF2BP2, which negatively regulate PD-L1 expression.
Impact: CDK5 plays a key role in medulloblastoma immune checkpoint regulation by promoting PD-L1 expression.
Cyclin-dependent kinase 5 (CDK5) is a serine–threonine kinase that plays a key role in central nervous system (CNS) development and has been implicated in angiogenesis, apoptosis, myogenesis, and senescence, suggesting it as a potential therapeutic target in cancer. Dorand and colleagues investigated the role of CDK5 in medulloblastoma, which is a malignant pediatric CNS tumor. CDK5 was expressed in medulloblastoma cell lines and clinical specimens. Depletion did not affect medulloblastoma cell proliferation in vitro, but increased tumor-free survival in medulloblastoma xenografts, and tumors that developed were smaller than in wild-type mice. Further, in human medulloblastomas, CDK5 depletion was associated with increased T-cell infiltration, altogether suggesting that CDK5 deficiency may promote T cell–dependent tumor rejection. In mouse CDK5-deficient medulloblastoma xenografts, depletion of CD4+ T cells reversed the effects of CDK5 depletion, resulting in accelerated tumor growth and tumor development in all mice. Additionally, the majority of mice that rejected CDK5-deficient tumors remained tumor free even after rechallenge with medulloblastoma cells, altogether supporting a CD4+ T cell–mediated rejection of CDK5-deficient tumors and the generation of antitumor immune memory. Interferon-γ (IFNγ) is a CD4+ T-cell effector cytokine that induces PD-L1, and it was highly expressed in CDK5-deficient tumors. Consistent with these findings, CDK5-deficient tumors exhibited decreased PD-L1 expression and reduced upregulation of PD-L1 in response to IFNγ. In wild-type cells, IFNγ stimulation downregulated IRF2 and IRF2BP2, both of which are transcriptional repressors of PD-L1. In contrast, in CDK5-deficient cells, IRF2BP2 hyperphosphorylation led to increased abundance of IRF2 and IRF2BP2. In vivo, orthotopic injection of CDK5-deficient medulloblastoma cells resulted in increased PD-L1 expression and a 50% tumor incidence, compared with 100% incidence in CDK5-proficient tumors. Collectively, these findings reveal a role for CDK5 in immune checkpoint regulation and suggest that CDK5-deficiency may enhance CD4+ T cell–mediated tumor cell killing by reducing PD-L1 expression.
Note: Research Watch is written by Cancer Discovery editorial staff. Readers are encouraged to consult the original articles for full details. For more Research Watch, visit Cancer Discovery online at http://cancerdiscovery.aacrjournals.org/content/early/by/section.