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.

Cyclin D–CDK4 kinase destabilizes PD-L1 via cullin 3–SPOP to control cancer immune surveillance

“…Although it has been reported that PD-L1 expression can be regulated at both transcriptional 9,10 and post-translational levels 11,12 , it remains unclear whether PD-L1 stability is regulated under physiological conditions such as during cell cycle progression. We found that PD-L1 protein abundance fluctuated during cell cycle in multiple human cancer cell lines, peaking in M/early G1 phases, followed by a sharp reduction in late G1/S phases (Fig.…”

Dinaciclib induces immunogenic cell death and enhances anti-PD1–mediated tumor suppression

“…Recently, Myc inactivation in tumor cells has been linked to downregulation of PD-L1 and CD47, molecules that normally would suppress both adaptive and innate antitumor responses (68). Similarly, CDK5 can phosphorylate Myc, and disruption of CDK5 has been linked to the downregulation of PD-L1 expression on medulloblastoma cells, leading to an enhanced immune response in the tumor (69,70). Conversely, some ICD inducers appear to increase the expression of checkpoint inhibitors and their ligands.…”

High response rate to PD-1 blockade in desmoplastic melanomas

“…Among DM cases for which we had exome sequencing, we did not detect many of the genetic mechanisms reported to cause constitutive PD-L1 expression, including amplification of the PD-L1/PD-L2/JAK2 (PDJ) locus or MYC, EGFR mutation or amplification, or CDK5 disruption. 21–24 The PD-L1 3′ UTR was not well captured in our exome sequencing, and disruption could not be assessed. 25 Therefore, the higher PD-L1 expression in DM is likely due to a reactive response to CD8 T cell infiltrates reflective of adaptive immune resistance.…”