Prostate cancer tumors can now be made vulnerable to immunotherapy using an experimental RNA-targeting technology developed by researchers, overcoming a major barrier that has historically left these malignancies “immune cold” and resistant to treatment.
Why Prostate Tumors Resist Immunotherapy
Most prostate tumors attract very few T cells, meaning the microscopic environment lacks enough infiltrating immune cells for immunotherapy to succeed, according to research published in Nature Biomedical Engineering. This immune cold state stems from a loss of the MHC-1 complex, a molecular signal that helps T cells recognize and destroy tumor cells. Scientists discovered that a protein named SPSB1 actively destroys the MHC-1 complex. In prostate cancer cells, the messenger RNA (mRNA) carrying the genetic instructions to create SPSB1 is abnormally shortened. Because shortened mRNAs have less exposed surface area and are more stable against internal cellular enzymes, they remain active for longer periods and produce excessive amounts of the SPSB1 protein, thereby eradicating the MHC-1 signal required to attract T cells.
CRISPR Technology Restores Immune Signaling
To reverse this process, a collaborative research team led by scientists at the Duke University School of Medicine engineered a first-of-its-kind therapy using an RNA-based CRISPR Cas13 system. Unlike traditional CRISPR tools that cut DNA or RNA, this experimental technology was designed to bind to a specific section of the shortened SPSB1 mRNA without cutting it, preventing cancer cells from shortening the tail of the molecule. By keeping the mRNA at its normal, longer length, the technology reduced SPSB1 protein production, allowing the MHC-1 complex to return to the cell surface.
Did you know? Messenger RNA (mRNA) carries genetic instructions from DNA to the cell’s protein-making machinery. When tumor cells shorten their mRNA, it acts much like an animal curling up for protection, making the molecule more stable and harder for the cell to regulate.
Preclinical Results and Future Testing
In laboratory studies of mice, restoring the MHC-1 complex significantly improved the response of prostate tumors to immune checkpoint therapy, allowing more immune cells to enter and destroy the cancer cells. Researchers performed a detailed analysis of the results and found no detectable off-target effects from the experimental CRISPR treatment. “No one has ever done this before. It’s an excellent preclinical model showing that mRNAs can be forced to re-lengthen and when they do, there’s therapeutic benefit,” said Eric J. Wagner, PhD, co-author of the study and professor of Biochemistry and Biophysics at the University of Rochester Medicine. Wagner and his team have received pilot funding from Wilmot and Roswell Park Comprehensive Cancer Center to test whether the approach can successfully re-sensitize pancreatic cancer, another immune cold tumor type, to immunotherapy.
Frequently Asked Questions
Why is prostate cancer considered immune cold?
Prostate cancer tumors are typically classified as immune cold because they attract very few T cells, largely due to the loss of the MHC-1 complex that helps the immune system identify and target malignant cells.
How does the new CRISPR tool work?
Unlike standard CRISPR systems that cut genetic material, this Cas13-based RNA-targeting tool attaches to specific sections of shortened mRNA molecules in cancer cells to prevent shortening, restoring normal protein levels and immune signaling.
What are the next steps for this research?
Following successful preclinical trials in mice with prostate cancer, researchers plan to test the RNA-lengthening technology in other immune-resistant tumor types, specifically pancreatic cancer.
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