CRISPR makes prostate cancer vulnerable to immunotherapy in mice
Researchers used a CRISPR-based tool to make "immune cold" prostate cancer vulnerable to immunotherapy in mice. The technology targets and re-lengthens a specific mRNA to restore the MHC-1 complex that immune cells use for recognition. Published in Nature Biomedical Engineering, the study showed this allowed immunotherapy to effectively destroy tumors, offering a new approach for cancers that resist such treatments.
CRISPR RNA targeting technology
▪The CRISPR Cas13 system was engineered to attach to a specific section of mRNA, preventing cancer cells from shortening its tail, rather than cutting it.
▪A detailed analysis of the experimental CRISPR treatment in the study found no detectable off-target effects.
▪Researchers developed an experimental RNA targeting technology using a CRISPR-based tool to make prostate tumors more vulnerable to an immune attack.
Prostate cancer immunotherapy resistance
▪A tumor can become immune cold due to the loss of the MHC-1 complex, a molecular signal that helps T cells recognize and kill tumor cells.
▪Prostate cancer is difficult to treat with immunotherapy because most of its tumors are "immune cold," attracting too few T cells to be effective.
Shortened mRNA in tumors
▪Shortened mRNAs are more stable and remain active longer, allowing them to produce large amounts of protein without normal cellular controls.
▪Researchers discovered 12 years ago that many mRNAs in tumor cells, such as in glioblastoma, were shorter than normal.
▪This mRNA shortening occurs across many cancer types and may help tumors adapt, survive, and escape treatment.
MHC-1 complex suppression mechanism
▪In prostate cancer, the mRNA that creates the SPSB1 protein is shortened, leading to an overproduction of SPSB1.
▪A specific protein called SPSB1 destroys the MHC-1 complex in cancer cells.
▪The overproduction of SPSB1 protein destroys the MHC-1 complex, making the tumor invisible to T cells and rendering immunotherapy futile.
Mouse model treatment results
▪The treatment restored the MHC-1 complex, causing more immune cells to enter the tumors and destroy cancer cells.
▪The findings of the study, led by scientists from Duke University School of Medicine, were published in Nature Biomedical Engineering.
▪In laboratory studies on mice, the CRISPR technology improved the response of prostate tumors to immune checkpoint therapy.
▪The research was funded by the National Cancer Institute at the National Institutes of Health.
Future pancreatic cancer testing
▪Researchers plan to investigate if the RNA-targeting approach can work in other immune cold cancers.
▪A team received pilot funding to test the technology in pancreatic cancer, another tumor type that often responds poorly to immunotherapy.
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