These days, scientists are fairly adept at reprogramming immune cell pathways to enhance the immune system’s own response to cancerous lesions, yet there is still a lack of understanding as to which specific circuits to rewire for the best results.
Fortunately, a new method called SLICE, which has been described in the 15 November issue of the science journal Cell, could provide scientists and physicians alike with the possibility of rapidly assessing every single gene located in the immune cells drawn from the patients themselves.
SLICE, which is based on the famed CRISPR technology, allows researchers to perform genome-wide screens of genetic changes to identify which genes have the biggest effect on the cellular behaviour of interest.
“We change one gene at a time in each cell and see which change causes the cell to do what we want it to. SLICE is the discovery engine that will point us towards pathways that we can reprogram to generate the most effective next-generation cell therapies,” said co-senior author on the study Alex Marson, MD, PhD.
As a proof of principle, the research team used SLICE to identify genes which promote the replication of T cells, and those which suppress it. Next, by deleting the inhibitory genes in patient-derived T cells via CRISPR, and culturing them in the presence of cancer, the team had found them to exhibit markedly improved cancer-fighting capacity.
With proof of principle out of the way, the team deployed SLICE to identify genes targeted by adenosine (a compound present in so-called “microenvironments”) and demonstrated that eliminating said genes allows T cells to successfully proliferate even in the presence of adenosine.
This is important because immunotherapy often fails precisely because of the various compounds present in the relevant cellular area (microenvironment) which prevent immune cells from maximising their potential for fighting malignancies.
The new technique utilises a recent discovery on the use of electroporation to deliver genetically engineered constructs back into the cell, produced by a lab headed by Alexdander Marson (one of the authors on the study), as well as more conventional methods based on viruses.
According to Marson, the future of SLICE may hold much more than what’s been described in the paper. “Given the flexibility of this approach, SLICE may one day help scientists to create personalised immune cells with novel disease-fighting properties.”