Joint release by Hokkaido University, Toyo University and University of Missouri
Researchers in Japan and the United States have developed a novel method for boosting the immune system’s capability to detect and eliminate cancer cells. This technology robustly augments the amount of an immune complex called MHC (major histocompatibility complex) class I in cancer cells.
“Our discovery has the potential to transform the way we approach cancer treatment,” said Hokkaido University immunologist Koichi Kobayashi, who led the study. “Our innovative 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.”
The technique reduced tumor sizes significantly and increased activity of immune cells called cytotoxic CD8+ T cells, the immune system’s primary cancer-fighting cells. , Known as TRED-I (Targeted Reactivation and Demethylation for MHC-I), it was tested in animal cancer models and markedly enhanced treatment efficacy when used in conjunction with existing immunotherapy.
“New modalities for fighting cancer like this are desperately needed because we have few solutions to fight some cancer types,” said Paul de Figueiredo, University of Missouri Bond Life Sciences Center researcher. “This is a radically new approach, and I’ve felt lucky to be part of it.”
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 from drawing the attention of cytotoxic CD8+ T cells. 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, called DNA methylation, in cancers to reduce MHC class I level. The TRED-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.
“This work is the result of our team’s research for over 10 years,” Kobayashi said. “It’s great to shed light on moving our findings to potential clinical application. We believe with further refinement, the TRED-I system could contribute significantly to cancer therapy.”
Further research could enable direct delivery of TRED-I system in cancer patients. If successful, such drugs could improve the efficacy for the immune system to eliminate cancer and able to improve the response to existing therapy.
The article “Targeted demethylation and activation of NLRC5 augment cancer immunogenicity through MHC class I” published in Proceedings of the National Academy of Sciences (PNAS) Feb. 1, 2024.
This work was supported by Japan Society for the Promotion of Science (JSPS) KAKEN grant 19K21250, 20K21511, 22H02883, 22KK0112; Japan Agency for Medical Research and Development (AMED) grant JP223fa627005 and 23ym0126801j0002; Japan Science and Technology (JST) START University Ecosystem Promotion Type grant JPMJST2284; Takeda Science Foundation; Bristol Myers Squibb; SENSHIN Medical Research Foundation; Hitachi Global Foundation; Kobayashi Foundation; The Toyo Suisan Foundation; KAKEN grant 20K16433; 19K16681