Prostate cancer is often highly resistant to immunotherapy because the tumors are typically “immune cold,” meaning they completely fail to attract the cancer-killing T cells needed to destroy them.
However, a cutting-edge new technology targeting RNA in cancer cells is giving immunotherapy new life.
Published in Nature Biomedical Engineering, a new study reveals how a CRISPR-based tool can alter cancer RNA, making prostate tumors act like magnets for immune cells. In laboratory tests on mice, the technology made tumors significantly more responsive to immune checkpoint therapy, successfully unleashing anti-tumor cells.
The underlying problem begins with the MHC-1 complex, a key cellular structure that signals to immune cells that a tumor is present. Without it, T cells simply cannot recognize or kill malignant cells. In prostate cancer, a specific protein called SPSB1 destroys this essential complex.
The research team discovered that the messenger RNA (mRNA) encoding the SPSB1 protein is abnormally shortened in cancer cells. Compact mRNAs are harder for cells to manage and control, allowing them to survive longer and drastically overproduce the SPSB1 protein. More SPSB1 directly leads to less MHC-1, rendering standard immunotherapy entirely ineffective.
To address this, researchers designed a first-of-its-kind therapy using an RNA-based CRISPR-Cas13 system. While traditional CRISPR typically cuts genetic material, this new system safely binds to a specific part of the mRNA and physically forces it to re-lengthen.
READ MORE: Lung transplants may save some cancer patients
Allowing the mRNA to maintain its normal length reduced SPSB1 protein levels and completely restored the vital MHC-1 complex. With the complex back online, immune therapy successfully infiltrated the tumors and destroyed the cancerous cells without causing harmful off-target effects.
“Cancer is super smart at evolving, but it’s not a magician,” said Eric J. Wagner, a study co-author from the University of Rochester. “If we can hit it with immunotherapy and another synergistic drug that pumps up the immune response, we could potentially cure it.”
After these highly successful preclinical trials, researchers plan to aggressively test the new CRISPR technology in other immune-cold diseases and have recently secured funding for a pilot study targeting pancreatic cancer.