Researchers in Japan and the United States have developed a new technology to increase visibility of cancer cells to the immune system using CRISPR. The findings were led by Koichi Kobayashi, professor at Hokkaido University and Texas A&M Health Center, and Paul de Figueiredo, Bond LSC principal investigator and NEXTGEN Precision Health endowed professor at the University of Missouri.
The new method is detailed in Proceedings of the National Academy of Sciences in an article titled, “Targeted demethylation and activation of NLRC5 augment cancer immunogenicity through MHC class I.”
Major histocompatibility complex (MHC) class I molecules are an immune complex present on the surface of all cells in humans. MHC class I molecules are a prerequisite for the immune system to recognize and eliminate cancer. When cancer cells are faced with pressure from the immune system, they actively reduce their MHC class I molecules, so cancer cells can hide.
The researchers developed their technology to robustly augment the amount of MHC class I in cancer cells.
“Our discovery has the potential to transform the way we approach cancer treatment,” explained Kobayashi. “Our technology enables us to specifically target immune responsive genes and activate the immune system against cancer cells, offering hope to those who are resistant to current immunotherapy.”
Kobayashi and his team previously identified a gene, called NLRC5, that regulates MHC class I levels. They further found that NLRC5 is suppressed by turning off molecular switches existing on DNA in cancers through DNA methylation to reduce levels of MHC class I.
Their technology, known as TRED-I (Targeted Reactivation and Demethylation for MHC-I) system, was able to restore DNA methylation of NLRC5 gene and further activate NLRC5, thus increasing MHC class I levels in cancer without causing severe side effects.
“New modalities for fighting cancer like this are desperately needed because we have few solutions to fight some cancer types,” said de Figueiredo. “This is a radically new approach, and I’ve felt lucky to be part of it.”
TRED-I was tested with animal cancer models. It reduced tumor sizes significantly and increased activity of cytotoxic CD8+ T cells. When used in conjunction with existing immunotherapy, TRED-I markedly enhanced treatment efficacy.
“This work is the culmination of our team’s research over the past decade,” Kobayashi concluded. “It’s great to shed light on moving our findings to potential clinical applications. We believe with further refinement, the TRED-I system could contribute significantly to cancer therapy.”
Their findings and method pave the way for new ways to combat cancer.