A new scientific study has characterised a checkpoint protein that allows certain brain tumour cells to avoid the immune system.
Tumours regularly avoid detection by decorating themselves with proteins that mimic those found on healthy cells.
This protective shield allows them to grow undetected, often with deadly results. Tumours regulate their defensive shields by coordinating cascades of protein signals.
These signals are often under the control of central coordinator proteins called serine/threonine kinases.
In the study published in Science, researchers studied a protein called cyclin-dependent kinase 5 (Cdk5), a serine/threonine kinase that is essential for nerve and tumour cell development.
The researchers specifically explored the role of Cdk5 in the development of medulloblastoma, a common, fast-growing paediatric brain tumour.
The researchers investigated Cdk5 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 Alex Huang, MD, PhD, associate professor of pediatrics, pathology, and biomedical engineering at the School of Medicine, and co-senior author of the study.
Agnes Petrosiute, MD, assistant professor of paediatrics at the School of Medicine, was the other senior author.
When the researchers blocked Cdk5 inside tumour cells and injected them into mice, more than half of the mice survived.
This suggested to the researchers that Cdk5 plays a central role in regulating the mice immune system response to tumours.
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 tumour cells and sparing the mice from tumours.
Human T cells with CD4 molecules on their surfaces communicate in part via an immune system signalling molecule called interferon-γ.
Many tumour cells disrupt this communication mechanism by expressing a molecule on their own surfaces called programmed cell death-ligand 1 (PD-L1).
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.
Tumour cells with PD-L1 on their surfaces can similarly deactivate T cells in their microenvironment and evade the immune system.
The researchers discovered that PD-L1 expression on tumour cells correlated with Cdk5 expression.
They tested several types of tumour cells without Cdk5 and found them unable to robustly produce PD-L1 on their surfaces in response to immune signaling molecules.
The researchers confirmed this by disrupting the PD-L1 gene in tumour cells directly.
Tumour cells without PD-L1 were unable to develop into lethal tumours in the majority of mice.
These findings clearly show a central role for Cdk5 in modulating a tumour’s ability to produce PD-L1.
“We discovered that Cdk5, a protein commonly expressed in abundance, controls how tumours produce an essential checkpoint molecule, PD-L1,” said Huang. “Our discovery opens the door for molecular therapies targeting Cdk5 and associated signalling pathways as an alternative to current therapies that often have severe side effects.”
The central role for Cdk5 in driving PD-L1 expression appears to be highly specific. Other proteins that act in response to immune signalling molecules were not affected by the lack of Cdk5 in tumour cells.
Immune signalling molecules have many functions beyond triggering Cdk5 (and ultimately PD-L1) expression on tumour cells.
The researchers used several techniques to tease apart the cascade of signals that connects immune signalling molecules to the tumour proteins. They identified 22 proteins that were differentially affected by the loss of Cdk5 in tumour cells, with a protein called IRF2BP2 most impacted. These proteins could potentially serve as therapeutic targets for anti-tumour medications in the future.
Approximately one-third of tumours can be combated by blocking PD-L1.
This study shows that blocking Cdk5 may be another way to block PD-L1 on the surfaces of tumours and recruit CD4 immune cells to shrink tumours.
Medulloblastoma accounts for approximately one-fifth of all paediatric brain tumours, according to the American Brain Tumour Association.
The vast majority of diagnoses occur in children under age 10 and surgery is the primary treatment mechanism.
[hr] Source: Science