A breakthrough for hard-to-treat tumors
Prostate cancer is notoriously difficult to treat with immunotherapy — most prostate tumors are considered "immune cold" because they attract very few T cells. Without enough T cells entering the tumor, immunotherapy has little chance of working.
Now, researchers have developed an experimental RNA-targeting technology that may make prostate tumors far more vulnerable to an immune attack. The findings, published in _Nature Biomedical Engineering_, showed that the technology improved the response of prostate tumors to immune checkpoint therapy in mice.
Why prostate cancer resists immunotherapy
The work grew out of a discovery made 12 years ago by Eric J. Wagner's team at the University of Rochester Medicine. While studying glioblastoma, researchers found that many mRNAs in tumor cells were shorter than normal. This shortening occurs across many types of cancer and may help tumors adapt, survive, and escape treatment.
One reason a tumor becomes immune cold is the loss of the MHC-1 complex — a molecular signal that helps T cells recognize tumor cells. The researchers uncovered a chain of events: a specific protein (SPSB1) destroys the MHC-1 complex. In prostate cancer, the mRNA carrying instructions to create SPSB1 is shortened, producing more protein. More SPSB1 means less MHC-1, making immune therapy futile.
CRISPR restores the tumor's immune magnet
The collaborative research team, led by scientists from Duke University School of Medicine, created a first-of-its-kind therapy using an RNA-based CRISPR Cas13 system. Unlike typical CRISPR tools that cut DNA or RNA, this system was engineered to attach to a specific section of the mRNA rather than cut it, preventing cancer cells from shortening the molecule.
Keeping the mRNA at its normal, longer length reduced SPSB1 protein production, allowing the MHC-1 complex to return. Once restored, immune checkpoint therapy became much more effective against the prostate tumors.
"Immune therapy 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 harm healthy cells in the process," said Wagner. "Our tool strengthens the immune system's ability to make the cancer go away."
Testing in other cold tumors
The researchers found no detectable off-target effects from the experimental CRISPR treatment. Wagner now plans to investigate whether the approach can work in other immune cold cancers, including pancreatic cancer, using pilot funding from Wilmot Cancer Institute and Roswell Park Comprehensive Cancer Center.
"Cancer is super smart at evolving, but it's not a magician. If we can hit it with immunotherapy and another synergistic drug that pumps up the immune response, we could potentially cure it," Wagner said.
