As new study led by investigators at Case Western Reserve University (CWRU) has pinpointed a cell-cycle checkpoint protein that allows individual brain tumor cells to avoid the immune system. Tumors often employ a common strategy of expressing surface proteins that are typically found on healthy cells—allowing them to grow virtually undetected. According to the American Brain Tumor Association, these cancers contribute to approximately 17,000 deaths annually, with over 4600 children newly diagnosed each year. So understanding the mechanism of how many of these tumors evade the immune system is imperative for efficacious treatment.
In this new study, the CWRU scientists studied a protein called cyclin-dependent kinase 5 (Cdk5), a serine/threonine kinase that is essential for nerve and tumor cell development. The researchers specifically explored the role of Cdk5 in the development of medulloblastoma (MB), a common, fast-growing pediatric brain tumor. The findings from the study were published recently in Science in an article entitled “Cdk5 Disruption Attenuates Tumor PD-L1 Expression and Promotes Antitumor Immunity.”
The researchers looked into Cdk5 as being a major player for immune avoidance because it is “commonly expressed in abundance and high Cdk5 levels correlate with a worse clinical prognosis in patients with melanoma, brain, breast, and lung cancers,” explained co-senior study author Alex Huang, M.D., Ph.D., associate professor of pediatrics, pathology, and biomedical engineering at CRWU School of Medicine.
The scientists found that when they blocked Cdk5 inside tumor cells and injected them into mice, more than half of the mice survived. Conversely, nearly all of the mice injected with tumor cells still containing Cdk5 died—suggesting that Cdk5 plays a central role in regulating the mice immune system response to tumors. Moreover, by systematically depleting subsets of white blood cells in the mice, the researchers were able to identify CD4+ T cells as the primary immune cells responsible for removing the Cdk5-deficient tumor cells and sparing the mice from tumors.
“We show that cyclin-dependent kinase 5 (Cdk5), a serine-threonine kinase that is highly active in postmitotic neurons and in many cancers, allows MB to evade immune elimination,” the authors wrote. “Interferon-γ (IFN-γ)–induced PD-L1 [programmed cell death ligand 1] 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.”
Many tumor cells disrupt the immune system communication mechanisms by expressing PD-L1 on the surface. Interestingly, the PD-L1 protein is also found on immune cells and normally helps “turn down” the immune system to avoid collateral damage once an immune response is complete. Tumor cells with PD-L1 on their surfaces can similarly deactivate T cells in their microenvironment and evade the immune system.
In their study, the research team found that PD-L1 expression on tumor cells correlated with Cdk5 expression. They tested several types of tumor cells without Cdk5 and found them unable to produce PD-L1 robustly on their surfaces in response to immune signaling molecules. Without Cdk5 or PD-L1, the tumor cells were much more vulnerable to the immune system. “Our finding highlights a central role for Cdk5 in immune checkpoint regulation by tumor cells,” the authors noted.
“We discovered that Cdk5, a protein commonly expressed in abundance, controls how tumors produce an essential checkpoint molecule, PD-L1,” remarked Dr. Huang. “Our discovery opens the door for molecular therapies targeting Cdk5 and associated signaling pathways as an alternative to current therapies that often have severe side effects.”
Approximately one-third of tumors can be combated by blocking PD-L1. This new study shows that blocking Cdk5 may potentially be another way to block PD-L1 on the surfaces of cancer cells and recruit CD4+ immune cells to shrink tumors. The researchers have characterized this pathway in medulloblastoma tumors, but preliminary evidence suggests it may also be applicable for other types of cancers.