Targeted demethylation and activation of NLRC5 augment cancer immunogenicity through MHC class I

• 成果类型: Article
• 署名作者: Sun, Xin; Watanabe, Toshiyuki; Oda, Yoshitaka; Shen, Weidong; Ahmad, Alaa; Ouda, Ryota; de Figueiredo, Paul; Kitamura, Hidemitsu; Tanaka, Shinya; Kobayashi, Koichi S.
• 署名单位: Hokkaido University; Hokkaido University; Hokkaido University; Texas A&M University System; Texas A&M University College Station; Texas A&M Health Science Center; University of Missouri System; University of Missouri Columbia; University of Missouri System; University of Missouri Columbia; University of Missouri System; University of Missouri Columbia; Toyo University; Hokkaido University; Hokkaido University
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-15428
• DOI: 10.1073/pnas.2310821121
• 发表日期: 2024-02-06
• 关键词: acquired-resistance; dna methylation; binding domain; pd-1 blockade; tumors; cells; immunization; regulator; immunity; complex

摘要

Impaired expression of MHC (major histocompatibility complex) class I in cancers constitutes a major mechanism of immune evasion. It has been well documented that the low level of MHC class I is associated with poor prognosis and resistance to checkpoint blockade therapies. However, there is lmited approaches to specifically induce MHC class I to date. Here, we show an approach for robust and specific induction of MHC class I by targeting an MHC class I transactivator (CITA)/NLRC5, using a CRISPR/Cas9-based gene- specific system, designated TRED-I (Targeted reactivation and demethylation for MHC-I). The TRED-I system specifically recruits a demethylating enzyme and transcriptional activators on the NLRC5 promoter, driving increased MHC class I antigen presentation and accelerated CD8+ T cell activation. Introduction of the TRED-I system in an animal cancer model exhibited tumor- suppressive effects accompanied with increased infiltration and activation of CD8+ T cells. Moreover, this approach boosted the efficacy of checkpoint blockade therapy using anti-PD1 (programmed cell death protein) antibody. Therefore, targeting NLRC5 by this strategy provides an attractive therapeutic approach for cancer. Significance MHC class I molecules are a key player in the human immune system and critical for detection and elimination of cancer cells. Although it has been known that augmented MHC class I expression is beneficial for cancer therapy, there has been limited approaches to specifically induce MHC class I. Here, we report specific and robust induction of MHC class I expression in cancer by applying a modified CRISPR/Cas9 technology for enhancement of the expression of MHC class I transactivator, also known as NLRC5. NLRC5 induction activated anticancer immunity, reduced tumor volume, and enhanced the efficacy of checkpoint blockade therapy. Therefore, targeting NLRC5 using this technology is a promising cancer therapeutic approach.