Prostate cancer is very 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 technology that can make prostate tumors much more vulnerable to immune attack.
Most prostate tumors are considered “immune colds” because they attract very few T cells (a type of immune cell). Without enough T cells entering the tumor, immunotherapy has little chance of working. In laboratory studies, scientists used a CRISPR-based tool to change RNA within prostate cancer cells, making tumors more visible and attractive to cancer-fighting immune cells.
The findings, published in Nature Biomedical Engineeringdemonstrated that the technology improved the response of prostate tumors to immune checkpoint therapy in mice. More immune cells entered the tumors, where they attacked and destroyed the cancer cells.
“Immunotherapy is a monumentally different way to treat cancer, and a great way because you don’t have to give patients terrible drugs that kill the cancer but damage healthy cells in the process,” said study co-author Eric J. Wagner, PhD, from the University of Rochester Medicine. “The problem is that some cancers respond well to immune therapy, but others develop resistance or do not respond at all. Our tool strengthens the immune system’s ability to make cancer go away and could be used in conjunction with existing immunotherapies in the prostate and potentially other types of cold immune tumors.”
Why prostate cancer resists immunotherapy
The work grew out of a discovery Wagner’s team made 12 years ago. While studying glioblastoma (brain cancer), researchers discovered that many mRNAs (messenger RNAs) in tumor cells were shorter than normal. Later studies by Wagner’s group and other scientists showed that this shortening occurs in many types of cancer and can help tumors adapt, survive, and escape treatment.
mRNA carries genetic instructions from DNA to the cell’s protein-making machinery, which converts the information into proteins the body needs to function. Shortened mRNAs tend to be more stable. Like animals that make themselves smaller to protect themselves (think hedgehogs and pangolins), compact mRNAs have less exposed surface area and are less likely to be “eaten up” by enzymes inside the cell.
Short mRNAs are also harder for cells to regulate. Because they remain active for longer periods, they can continue to produce large amounts of proteins and extend their effects without normal cellular controls.
The immune signal that cancer cells destroy
One of the reasons a tumor can become immune is the loss of the MHC-1 complex. This complex acts as a molecular signal that helps T cells recognize tumor cells. Without it, malignant cells become much more difficult for the immune system to identify and eliminate.
Researchers discovered a chain of events that helps explain how prostate cancer turns off this signal:
- There is a specific protein (SPSB1) that destroys the MHC-1 complex.
- In prostate cancer, the mRNA that carries the instructions to create this protein is shortened. Consequently, it produces more protein.
- More SPSB1 protein means less MHC-1 complex.
- Less MHC-1 complex makes immune therapy useless, because there is no magnet to attract T cells to the tumor.
CRISPR restores tumor immune magnet
The collaborative research team, led by scientists at Duke University School of Medicine, created a first-of-its-kind therapy designed to restore the normal length of the mRNA that SPSB1 produces. Using an RNA-based CRISPR Cas13 system, the researchers forced the shortened SPSB1 mRNA to lengthen again.
CRISPR tools typically work by cutting DNA or RNA. In this case, however, the system was designed to bind to a specific section of the mRNA rather than cutting it. By binding to that location, the tool prevented cancer cells from reaching and shortening the end, or tail, of the molecule.
Keeping the mRNA at its normal, longer length reduced the amount of SPSB1 protein produced by the cancer cells. This allowed the MHC-1 complex to return.
Once the MHC-1 complex was restored, immune checkpoint therapy became much more effective against prostate tumors. The researchers also performed a detailed analysis of the results and found no detectable off-target effects of the experimental CRISPR treatment.
“No one has done this before. It’s an excellent preclinical model that shows that you can force mRNAs to elongate again, and when they do, there is a therapeutic benefit,” said Wagner, professor of Biochemistry and Biophysics and co-director of the Center for RNA Biology. “Cancer is very intelligent at evolving, but it is not a magician. If we can attack it with immunotherapy and another synergistic drug that increases the immune response, we could potentially cure it. It cannot evolve fast enough.”
Testing the technology in 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 the approach can work in other cold immune cancers.
His team recently received pilot funding from Wilmot and Roswell Park Comprehensive Cancer Center to test the technology in pancreatic cancer, another type of tumor that often responds poorly to immunotherapy.
The research was funded by the National Cancer Institute of the National Institutes of Health.