Researchers report that an RNA-targeting CRISPR-Cas13 system can reverse a prostate cancer immune-evasion mechanism by restoring MHC-I on tumor cells, improving responses to immune checkpoint therapy in mice. The study was published in Nature Biomedical Engineering.
Prostate cancer has been difficult to treat with immunotherapy because many tumors are considered “immune cold,” meaning they draw in few T cells—immune cells needed for many checkpoint therapies to work.
In a study published in Nature Biomedical Engineering, scientists described an experimental approach that targets how tumor cells process the messenger RNA (mRNA) for a protein called SPSB1. According to the researchers, prostate cancer cells can shorten the SPSB1 mRNA, which increases SPSB1 protein levels. SPSB1, in turn, contributes to loss of the MHC-I complex—an important cell-surface signal that helps T cells recognize cancer cells.
To counter this, the team used an RNA-based CRISPR system built around Cas13 that was engineered to bind a specific region of the SPSB1 mRNA rather than cut it. By blocking access to the mRNA’s tail region, the method forced the shortened SPSB1 mRNA to “re-lengthen,” reducing SPSB1 protein levels and allowing MHC-I to return on the cancer-cell surface.
In mouse experiments, restoring MHC-I made immune checkpoint therapy more effective: more immune cells infiltrated tumors and attacked cancer cells. The researchers also reported that their analyses found no detectable off-target effects from the CRISPR-based treatment.
“Immune therapy is a monumentally different way to treat cancer… Our tool strengthens the immune system’s ability to make the cancer go away and could be used in conjunction with existing immunotherapies in prostate and potentially other immune-cold tumor types,” said Eric J. Wagner, a co-author from the University of Rochester Medicine.
The collaborative research group was led by scientists from Duke University School of Medicine, the University of Rochester Medicine said. The work was funded by the National Cancer Institute, part of the U.S. National Institutes of Health.
Wagner’s team plans to test whether the approach can help in other immune-cold cancers. The University of Rochester Medicine said the group has received pilot funding from Wilmot Cancer Institute and Roswell Park Comprehensive Cancer Center to explore the technology in pancreatic cancer.
