Emerging data support a critical role for PD-L1/PD-1 signaling in tumor immunity, with approximately 30-50% of tumors responding to immune checkpoint blockade. Cdk5 has been targeted in cancer, but its immune-modulatory role has not been explored. Our accumulating data point to an important role of Cdk5 disruption in sensitizing medulloblastoma to CD4+ T cell dependent rejection by inhibiting tumor PD-L1 expression in response to interferon-gamma stimulation, a process associated with hyper-phosphorylation of S440 and S443 on IRF2BP2, a corepressor in complex with IRF2 to suppress PD-L1 gene transcription. In Aim 1, we propose to study the molecular mechanism underlying hyper-phosphorylation of S440 and S443 in the absence of Cdk5, including hyper activation of GSK3 and ERK1/2. Continuing our molecular pursuit may yield opportunities to modulate tumor immunity while limit toxicity of systemic checkpoint blockade. We have also identified a newer, more potent next-generation Cdk5 inhibitor, CYC065, which may exhibit enhanced inhibitory activity against PD-L1 expression in MB.
We are in discussion with Cyclacel, Ltd. who will provide CYC065 for preclinical study in Aim 2 as well as Phase 1 clinical trials in AYA Medulloblastoma in the very near future based on findings of this grant.