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

ABSTRACT: Impaired expression of MHC class I constitutes a major mechanism of immune evasion of cancers, leading to poor prognosis and resistance to checkpoint blockade therapies. Existing drugs for MHC class I have limited applicability due to severe side effects. Here we show a novel approach of robust and specific induction of MHC class I by targeting an MHC class I transactivator (CITA), NLRC5, using a CRISPR/Cas9 based gene-specific targeted demethylaion (TDM) system and targeted demethylation and activation (TDMa) system. The TDMa system specifically recruits a demethylating enzyme and transcriptional activators, providing efficient demethylation and transactivation of the NLRC5 promoter. TDMa in mouse and human cancer cells induced MHC class I antigen presentation and accelerated CD8+ T cell activation with tumor suppression effects both in vitro and in vivo. Moreover, enhanced immunogenicity by NLRC5 TDMa boosted efficacy of anti-PD1 therapy. Therefore, NLRC5 targeting by the TDMa system confers an attractive therapeutic approach against cancer.

ORGANISM(S): Mus musculus

PROVIDER: GSE233194 | GEO | 2024/02/22

REPOSITORIES: GEO

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NLRC5 specifically transactivates MHC class I and related genes through a distinctive SXY module

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