Researchers at the University of California have developed a CRISPR-based tool called SLICE that can boost the effectiveness of immune cell therapies.
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Scientists have become expert at manipulating the immune system to target and kill cancer, but although they understand how to reprogram immune cell pathways, they often cannot pinpoint which circuits need rewiring to make immune defense more effective.
Now, Alex Marson and colleagues have created a tool called SLICE that reveals the function of every gene in immune cells, enabling researchers to see how to best engineer cells that will fight cancer and other diseases.
SLICE allows us to perform genome-wide screens in which we mutate every gene in the genome to see which genes have the biggest effect on the cellular behavior we're interested in.”
Alex Marson, Study Lead
By changing one gene at a time in each cell and seeing which changes cause the cell to do what the researchers want it to do, SLICE can indicate which pathways can be reprogrammed to generate the most potent next-generation cell therapies.
Given that cancer immunotherapy uses artificially stimulated T cells to fight cancer, the team decided to test whether SLICE could be used to identify genes that enhance the replication of T cells.
As recently reported in the journal Cell, SLICE enabled the researchers to identify genes that promote this replication, as well as the genes that suppress it.
Next, the team obtained primary T cells from donors and deleted the genes that were found to suppress replication.
On growing the SLICE-modified T cells in the presence of cancer, the researchers found that the cells had a significantly improved ability to kill cancer, meaning that the genes identified can be edited to transform normal T cells into a potentially highly effective therapy.
However, cancer has an ability to thrive in environments where T cells are suppressed by compounds that prevent their cancer-killing potential, so Marson and team wanted to know whether SLICE could be used to overcome this suppression.
Using the new tool, the team identified genes that are targeted by the adenosine, an immunosuppressor commonly found in tumor microenvironments. They then showed that deleting those genes results in T cell proliferation, even when adenosine is present.
SLICE functions as a flexible platform that allows scientists to model the interaction between immune cells and the tumor microenvironment.
We've shown that SLICE can help researchers identify genes that allow immune cells to escape the immunosuppressive forces they encounter in these microenvironments."
Alan Ashworth, Co-senior Author
Marson adds that the potential applications for SLICE are not limited to what's described in this study: "Given the flexibility of this approach, SLICE may one day help scientists to create personalized immune cells with novel disease-fighting properties."