Prostate cancer is notoriously difficult to treat with immunotherapy, a type of cancer treatment that helps the immune system identify and destroy tumors. Now, researchers have developed an experimental RNA targeting technique that could make prostate tumors much more vulnerable to immune attack.
Most prostate tumors are considered “immune colds” because they attract few T cells (a type of immune cell). Without enough T cells infiltrating the tumor, immunotherapy is unlikely to be effective. In laboratory studies, scientists used CRISPR-based tools to alter RNA within prostate cancer cells, effectively making the tumors more visible and attractive to cancer-fighting immune cells.
The survey results are natural biomedical engineeringshowed that this technique improved the response of prostate tumors to immune checkpoint therapy in mice. More immune cells enter the tumor and attack and destroy cancer cells.
“Immunotherapy is a completely different way of treating cancer, and it’s great because it doesn’t require patients to be given terrible drugs that kill cancer but harm healthy cells in the process,” said co-author Eric J. Wagner, Ph.D., of the Rochester School of Medicine. “The problem is that some cancers respond well to immunotherapy, while others develop resistance or don’t respond at all. Our tool enhances the immune system’s ability to kill cancer and could be used in conjunction with existing immunotherapies in prostate and potentially other immune system tumor types.”
Why prostate cancer resists immunotherapy
The work grew out of a discovery Wagner’s team made 12 years ago. While studying glioblastoma (a brain tumor), researchers discovered that many mRNAs (messenger RNAs) in tumor cells are shorter than normal. Subsequent research by Wagner’s group and other scientists showed that this shortening occurs in many types of cancer and may help tumors adapt, survive and evade treatment.
mRNA carries genetic instructions from DNA to the cell’s protein-making machinery, which converts that information into the proteins the body needs to function. Shortened mRNAs tend to be more stable. Similar to animals that shrink to protect themselves (think hedgehogs and pangolins), compact mRNAs have less exposed surface area and are less likely to be “eaten” by enzymes in cells.
Shorter mRNAs are also more difficult to regulate by cells. Because they remain active for longer periods of time, they can continue to produce large amounts of protein and their effects can spread without normal cellular control.
Immune signals destroyed by cancer cells
One of the reasons why tumors become immunoderanged is the loss of MHC-1 complexes. This complex acts like a molecular signal that helps T cells recognize tumor cells. Without this, it would be much harder for the immune system to identify and kill malignant cells.
Researchers discovered a series of events that help explain how prostate cancer blocks this signal.
- There is a specific protein (SPSB1) that disrupts the MHC-1 complex.
- In prostate cancer, the mRNA that carries the instructions to make this protein is shortened. As a result, more protein is produced.
- The more SPSB1 protein there is, the less MHC-1 complexes there are.
- When MHC-1 complexes are low, there is no magnet to attract T cells to the tumor, making immunotherapy futile.
CRISPR restores tumor immunomagnetism
A collaborative research team led by scientists at Duke University School of Medicine has developed a first-of-its-kind treatment aimed at restoring the mRNA that produces SPSB1 to its normal length. The researchers used the RNA-based CRISPR Cas13 system to force re-lengthen the truncated SPSB1 mRNA.
CRISPR tools often work by cutting DNA or RNA. However, in this case, the system is designed to bind to specific parts of the mRNA rather than cutting it. By binding in place, the tool prevented cancer cells from reaching and shortening the end, or tail, of the molecule.
Keeping the mRNA at a longer than normal length reduced the amount of SPSB1 protein produced by cancer cells. This allowed the MHC-1 complex to return.
Once the MHC-1 complex was restored, immune checkpoint therapy became more effective against prostate tumors. The researchers also conducted 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. This is a great preclinical model to show that you can force mRNA to re-extend, and when you re-extend it, it has a therapeutic effect,” said Wagner, professor of biochemistry and biophysics and co-director of the Center for RNA Biology. “Cancers evolve very smartly, but they’re not magicians. If we can attack them with immunotherapy and another synergistic drug that boosts the immune response, we might be able to cure them. Cancers can’t evolve fast enough.”
Testing the technology on other cold tumors
Wagner, who is also a member of the Wilmot Cancer Institute’s Genetics, Epigenetics, and Metabolism Research Program, now plans to investigate whether this approach also works for other immune-mediated cold cancers.
His team recently received pilot funding from Wilmot Roswell Park Comprehensive Cancer Center to test the technology in pancreatic cancer, another tumor type that responds poorly to immunotherapy.
This study was funded by the National Cancer Institute of the National Institutes of Health.
