A new technology has been developed to increase the visibility of cancer cells to the immune system using CRISPR, and it could lead to a new way to treat cancer.
The major histocompatibility complex (MHC) class I molecule is an immune complex present on the surface of all human cells. MHC class I molecules are a prerequisite for the immune system to recognize and eliminate cancer. When cancer cells encounter stress from the immune system, they actively downregulate their MHC class I molecules, so the cancer cells can hide from the attention of CD8+ T cells, the immune system’s primary cancer-fighting cells.
Researchers from Japan and the United States led by Professor Koichi Kobayashi of Hokkaido University and Texas A&M Health Center and Dr. Paul de Figueiredo, Bond LSC principal investigator and NextGen Precision Health Professor at the University of Missouri, developed technology to robustly increase the amount of MHC class I in cancer cells. The development, a novel approach to enhancing the immune system’s ability to detect and eliminate cancer cells, was published in the journal Proceedings of the National Academy of Sciences.
Our discovery has the potential to change the way cancer is treated. Our technology enables us to specifically target immune responsive genes and activate the immune system against cancer cells, offering hope for those resistant to current immunotherapies.”
Professor Koichi Kobayashi of Hokkaido University
Kobayashi and his team previously identified a gene called NLRC5, which regulates MHC class I levels. They also found that NLRC5 is suppressed in cancer by turning off molecular switches in DNA—through a process called DNA methylation—to reduce MHC class I levels.
Their technology, called the TRED-I (Targeted Reactivation and Demethylation for MHC-I) system, was able to restore DNA methylation of the NLRC5 gene and further activate NLRC5, thus increasing MHC class I levels in cancer without causing serious side effects.
“New approaches like this are desperately needed to fight cancer because we have very few solutions to fight certain types of cancer,” said de Figueiredo. “It’s a radical new approach, and I feel lucky to be a part of it.”
TRED-I was tested in animal cancer models. It significantly reduced tumor size and increased cytotoxic CD8+ T cell activity. When used in combination with existing immunotherapies, TRED-I markedly improved treatment efficacy.
Unexpectedly, the TRED-I system was effective for tumors located far from the original target tumor, showing potential for treatment of metastasized cancer.
“This work is the culmination of our team’s research over the past decade,” Kobayashi concluded. “It is great to shed light on moving our findings into potential clinical applications. We believe with further refinement, the TRED-I system could significantly contribute to cancer therapy.”
Further research will focus on enabling direct delivery of the TRED-I system to cancer patients. Such drugs may improve the immune system’s ability to eradicate cancer and may also improve response to existing therapies.
Surya, X., etc (2024) Targeted demethylation and activation of NLRC5 enhances cancer immunogenicity through MHC class I. PNAS. DOI: 10.1073/pnas.2310821121.