Development of novel epigenetic editing technology for the immune checkpoint therapy of cancers

2021 Fiscal Year Final Research Report

• Project/Area Number: 20K16433
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 50020:Tumor diagnostics and therapeutics-related
• Research Institution: Hokkaido University
• Principal Investigator: Watanabe Toshiyuki 北海道大学, 医学研究院, 客員研究員 (10843435)
• Project Period (FY): 2020-04-01 – 2022-03-31
• Keywords: MHC class I / NLRC5 / promoter / DNA methylation

Outline of Final Research Achievements

It has been demonstrated that many cancers escape from the human immune system by reducing MHC class I expression via promoter methylation of NLRC5 gene, a master coactivator of MHC class I genes. By employing defective Cas9 (dCas9) and demethylating enzyme TET1, we have succeeded in introducing demethylation on the promoter of NLRC5, and subsequent induction of NLRC5 and MHC class I genes. We could further enhance the expression level by appending the transactivator components which activates promoter in the gRNA-based sequence specific manner. These technologies are not only useful for lung cancer treatments but also other cancers and non-cancerous disorders.

Free Research Field

免疫学

Academic Significance and Societal Importance of the Research Achievements

癌におけるDNAメチル化は以前よりよく知られている。実際に脱メチル化を行う薬剤が癌治療に使われてきている。しかしながら従来の脱メチル化剤は、特異性が低く副作用が大きいため、臨床応用が難しく、ごく限られた癌腫にのみ適用がある。遺伝子特異的な脱メチル化技術は副作用が低いことが期待される上、数多くの標的遺伝子を選択することができることから、多くの癌腫に応用可能であり、これから多くの治療技術の基盤技術となる可能性が高い。